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In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bromodomain 4 (BRD4), a key regulator with pleiotropic functions, plays crucial roles in cancers and cellular stress responses. It exhibits dual functionality: chromatin-bound BRD4 regulates remodeling through its histone acetyltransferase (HAT) activity, while promoter-associated BRD4 regulates transcription through its kinase activity. Notably, chromatin-bound BRD4 lacks kinase activity, and RNA polymerase II (RNA Pol II)-bound BRD4 exhibits no HAT activity. This study unveils one mechanism underlying BRD4's functional switch. In response to diverse stimuli, c-Jun N-terminal kinase (JNK)-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its kinase activity. Released BRD4 directly interacts with and phosphorylates RNA Pol II, PTEFb, and c-Myc, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both lamtor1 mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates lamtor1 transcription, we cloned the deletion mutants of the lamtor1 promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone 3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH 4 Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. In vivo, LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO 3 -injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances lamtor1 transcription. This study reveals a previously unrecognized regulatory mechanism of lamtor1 by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests that chromatin-modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and cAMP-response element binding protein (CREB)-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue- and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using uncoupling protein 1 ( Ucp1 ) - Cre-mediated knockdown in mice to determine whether their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via β 3 -agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the β 3 -adrenergic agonist CL-316,243 remained largely intact in knockout mice. Although p300 and CBP have nonoverlapping roles in other tissues, our results indicate that they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another. NEW & NOTEWORTHY The role of transcriptionally activating H3K27ac epigenetic mark has yet to be examined in mouse thermogenic fats specifically, which we achieved here via Ucp1 -Cre-driven knockdown of the histone acetyltransferases (HAT) p300 or CBP under several metabolic contexts. Despite successful knockdown of either HAT, brown adipose tissue was maintained at room temperature. As such, knockout mice were indistinguishable to controls when fed an obesogenic diet or when given a β 3 -adrenergic receptor agonist to induce browning of white fat. Unlike other tissues, thermogenic fats are resilient to p300 or CBP ablation, likely due to sufficient functional overlap between them.

p53 expression and acetylation are crucial for the survival and death of neurons in penumbra. At the same time, the outcome of ischemia for penumbra cells depends largely on the histone acetylation status, but the effect of histone acetyltransferases and deacetylases on non-histone proteins like p53 is largely understudied. With combined in silico and in vitro approach, we have identified enzymes capable of acetylation/deacetylation, distribution, stability, and pro-apoptotic activity of p53 in ischemic penumbra in the course of post-stroke recovery, and also detected involved loci of acetylation in p53. The dynamic regulation of the acetylation of p53 at lysine 320 is controlled by acetyltransferase PCAF and histone deacetylases HDAC1 and HDAC6. The in silico simulation have made it possible to suggest the acetylation of p53 at lysine 320 acetylation may facilitate the shuttling of p53 between the nucleus and cytoplasm in penumbra neurons. Acetylation of p53 at lysine 320 is more preferable than acetylation at lysine 373 and probably promotes survival and repair of penumbra neurons after stroke. Strategies to increase p53 acetylation at lysine 320 via increasing PCAF activity, inhibiting HDAC1 or HDAC6, inhibiting p53, or a combination of these interventions may have therapeutic benefits for stroke recovery and would be promising for neuroprotective therapy of stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Some cancer types including bladder, cervical, and uterine cancers are characterized by frequent mutations in EP300 that encode histone acetyltransferase p300. This enzyme can act both as a tumor suppressor and oncogene. In this review, we describe the role of p300 in cancer initiation and progression regarding EP300 aberrations that have been identified in TGCA Pan-Cancer Atlas studies and we also discuss possible anticancer strategies that target EP300 mutated cancers. Copy number alterations, truncating mutations, and abnormal EP300 transcriptions that affect p300 abundance and activity are associated with several pathological features such as tumor grading, metastases, and patient survival. Elevated EP300 correlates with a higher mRNA level of other epigenetic factors and chromatin remodeling enzymes that co-operate with p300 in creating permissive conditions for malignant transformation, tumor growth and metastases. The status of EP300 expression can be considered as a prognostic marker for anticancer immunotherapy efficacy, as EP300 mutations are followed by an increased expression of PDL-1.HAT activators such as CTB or YF2 can be applied for p300-deficient patients, whereas the natural and synthetic inhibitors of p300 activity, as well as dual HAT/bromodomain inhibitors and the PROTAC degradation of p300, may serve as strategies in the fight against p300-fueled cancers., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The Eaf6 protein, a conserved component of the NuA4 and NuA3 complexes in yeast and MOZ/MORF complexes in humans, plays crucial roles in transcriptional activation, gene regulation, and cell cycle control. Despite its significance in other organisms, the functional role of Eaf6 in entomopathogenic fungi (EPF) remained unexplored. Here, we investigate the function of BbEaf6, the Eaf6 homolog in the entomopathogenic fungus Beauveria bassiana . We demonstrate that BbEaf6 is predominantly localized in nuclei, similar to its counterpart in other fungi. Deletion of BbEaf6 resulted in delayed conidiation, reduced conidial yield, and altered conidial properties. Transcriptomic analysis revealed dysregulation of the genes involved in asexual development and cell cycle progression in the Δ BbEaf6 mutant. Furthermore, the Δ BbEaf6 mutant exhibited decreased tolerance to various stresses, including ionic stress, cell wall perturbation, and DNA damage stress. Notably, the Δ BbEaf6 mutant displayed attenuated virulence in insect bioassays, accompanied by dysregulation of genes associated with cuticle penetration and haemocoel infection. Overall, our study elucidates the multifaceted role of BbEaf6 in stress response, development, and virulence in B. bassiana , providing valuable insights into the molecular mechanisms governing fungal pathogenesis and potential targets for pest management strategies.

In eukaryotes, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are reversibly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence highlights histone acetylation plays essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance of histone acetylation in the regulation of abiotic stress responses including temperature, light, salt and drought stress. This information will contribute to our understanding of how plants adapt to environmental changes. As the mechanisms of epigenetic regulation are conserved in many plants, research in this field has potential applications in improvement of agricultural productivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Li, Liu, He, Li, Guo, Zhang, Zhao and Guo.)

Background: Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are involved in plant growth and development as well as in response to environmental changes, by dynamically regulating gene acetylation levels. Although there have been numerous reports on the identification and function of HDAC and HAT in herbaceous plants, there are fewer report related genes in woody plants under drought stress., Results: In this study, we performed a genome-wide analysis of the HDAC and HAT families in Populus trichocarpa, including phylogenetic analysis, gene structure, conserved domains, and expression analysis. A total of 16 PtrHDACs and 12 PtrHATs were identified in P. trichocarpa genome. Analysis of cis-elements in the promoters of PtrHDACs and PtrHATs revealed that both gene families could respond to a variety of environmental signals, including hormones and drought. Furthermore, real time quantitative PCR indicated that PtrHDA906 and PtrHAG3 were significantly responsive to drought. PtrHDA906, PtrHAC1, PtrHAC3, PtrHAG2, PtrHAG6 and PtrHAF1 consistently responded to abscisic acid, methyl jasmonate and salicylic acid under drought conditions., Conclusions: Our study demonstrates that PtrHDACs and PtrHATs may respond to drought through hormone signaling pathways, which helps to reveal the hub of acetylation modification in hormone regulation of abiotic stress., (© 2024. The Author(s).)

Background: Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with poor prognosis. Further mechanistic insights into the molecular mechanisms of CCA are needed to develop more effective target therapy., Methods: The expression of the histone lysine acetyltransferase KAT2B in human CCA was analyzed in human CCA tissues. CCA xenograft was developed by inoculation of human CCA cells with or without KAT2B overexpression into SCID mice. Western blotting, ChIP-qPCR, qRT-PCR, protein immunoprecipitation, GST pull-down and RNA-seq were performed to delineate KAT2B mechanisms of action in CCA., Results: We identified KAT2B as a frequently downregulated histone acetyltransferase in human CCA. Downregulation of KAT2B was significantly associated with CCA disease progression and poor prognosis of CCA patients. The reduction of KAT2B expression in human CCA was attributed to gene copy number loss. In experimental systems, we demonstrated that overexpression of KAT2B suppressed CCA cell proliferation and colony formation in vitro and inhibits CCA growth in mice. Mechanistically, forced overexpression of KAT2B enhanced the expression of the tumor suppressor gene NF2, which is independent of its histone acetyltransferase activity. We showed that KAT2B was recruited to the promoter region of the NF2 gene via interaction with the transcription factor SP1, which led to enhanced transcription of the NF2 gene. KAT2B-induced NF2 resulted in subsequent inhibition of YAP activity, as reflected by reduced nuclear accumulation of oncogenic YAP and inhibition of YAP downstream genes. Depletion of NF2 was able to reverse KAT2B-induced reduction of nuclear YAP and subvert KAT2B-induced inhibition of CCA cell growth., Conclusions: This study provides the first evidence for an important tumor inhibitory effect of KAT2B in CCA through regulation of NF2-YAP signaling and suggests that this signaling cascade may be therapeutically targeted for CCA treatment., (© 2024. The Author(s).)

Histone acetyltransferase (HAT)-mediated epigenetic modification is essential for diverse cellular processes in eukaryotes. However, the functions of HATs in the human pathogen Aspergillus fumigatus remain poorly understood. In this study, we characterized the functions of M OZ, Y bf2/ S as3, Sas2, and T ip60 (MYST)-family histone acetyltransferase something about silencing (Sas3) in A. fumigatus . Phenotypic analysis revealed that loss of Sas3 results in significant impairments in colony growth, conidiation, and virulence in the Galleria mellonella model. Subcellular localization and Western blot analysis demonstrated that Sas3 localizes to nuclei and is capable of acetylating lysine 9 and 14 of histone H3 in vivo . Importantly, we found that Sas3 is critical for the cell wall integrity (CWI) pathway in A. fumigatus as evidenced by hypersensitivity to cell wall-perturbing agents, altered cell wall thickness, and abnormal phosphorylation levels of CWI protein kinase MpkA. Furthermore, site-directed mutagenesis studies revealed that the conserved glycine residues G641 and G643 and glutamate residue E664 are crucial for the acetylation activity of Sas3. Unexpectedly, only triple mutations of Sas3 (G641A/G643A/E664A) displayed defective phenotypes similar to the Δ sas3 mutant, while double or single mutations did not. This result implies that the role of Sas3 may extend beyond histone acetylation. Collectively, our findings demonstrate that MYST-family HAT Sas3 plays an important role in the fungal development, virulence, and cell wall integrity in A. fumigatus ., Importance: Epigenetic modification governed by HATs is indispensable for various cellular processes in eukaryotes. Nonetheless, the precise functions of HATs in the human pathogen Aspergillus fumigatus remain elusive. In this study, we unveil the roles of MYST-family HAT Sas3 in colony growth, conidiation, virulence, and cell wall stress response in A. fumigatus . Particularly, our findings demonstrate that Sas3 can function through mechanisms unrelated to histone acetylation, as evidenced by site-directed mutagenesis experiments. Overall, this study broadens our understanding of the regulatory mechanism of HATs in fungal pathogens., Competing Interests: The authors declare no conflict of interest.

The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing hematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined the role of KAT6B in the hematopoietic system. We found that KAT6B sustained the fetal hematopoietic stem cell pool but did not affect viability or differentiation. KAT6B was essential for normal levels of histone H3 lysine 9 (H3K9) acetylation but not for a previously proposed target, H3K23. Compound heterozygosity of Kat6b and the closely related gene, Kat6a, abolished hematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promoted transcription of genes regulating hematopoiesis, including the Hoxa cluster, Pbx1, Meis1, Gata family, Erg, and Flt3. In conclusion, we identified the hematopoietic processes requiring Kat6b and showed that KAT6B and KAT6A synergistically promoted HSC development, function, and transcription. Our findings are pertinent to current clinical trials testing KAT6A/B inhibitors as cancer therapeutics., Competing Interests: Declaration of interests T.T. and A.K.V. are inventors on patent WO2016198507 A1. The Thomas and Voss laboratories received research funding from the CRC for Cancer Therapeutics (CTx), Australia. T.T. and A.K.V. have received payments from a distribution of licensing income from Pfizer and have served on an advisory board for Pfizer., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pollinators are vital for food security and the maintenance of terrestrial ecosystems. Bumblebees are important pollinators across northern temperate, arctic, and alpine ecosystems, yet are in decline across the globe. Vairimorpha bombi is a parasite belonging to the fungal class Microsporidia that has been implicated in the rapid decline of bumblebees in North America, where it may be an emerging infectious disease. To investigate the evolutionary basis of pathogenicity of V. bombi, we sequenced and assembled its genome using Oxford Nanopore and Illumina technologies and performed phylogenetic and genomic evolutionary analyses. The genome assembly for V. bombi is 4.73 Mb, from which we predicted 1,870 protein-coding genes and 179 tRNA genes. The genome assembly has low repetitive content and low GC content. V. bombi's genome assembly is the smallest of the Vairimorpha and closely related Nosema genera, but larger than those found in the Encephalitozoon and Ordospora sister clades. Orthology and phylogenetic analysis revealed 18 core conserved single-copy microsporidian genes including the histone acetyltransferase (HAT) GCN5. Surprisingly, V. bombi was unique to the microsporidia in not encoding the second predicted HAT ESA1. The V. bombi genome assembly annotation included 265 unique genes (i.e. not predicted in other microsporidia genome assemblies), 20% of which encode a secretion signal, which is a significant enrichment. Intriguingly, of the 36 microsporidian genomes we analyzed, 26 also had a significant enrichment of secreted signals encoded by unique genes, ranging from 6 to 71% of those predicted genes. These results suggest that microsporidia are under selection to generate and purge diverse and unique genes encoding secreted proteins, potentially contributing to or facilitating infection of their diverse hosts. Furthermore, V. bombi has 5/7 conserved spore wall proteins (SWPs) with its closest relative V. ceranae (that primarily infects honeybees), while also uniquely encoding four additional SWPs. This gene class is thought to be essential for infection, providing both environmental protection and recognition and uptake into the host cell. Together, our results show that SWPs and unique genes encoding a secretion signal are rapidly evolving in the microsporidia, suggesting that they underpin key pathobiological traits including host specificity and pathogenicity., Competing Interests: Conflicts of interest. The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

In Saccharomyces cerevisiae, boundaries formed by DNA sequence-dependent or -independent histone modifications stop the spread of the heterochromatin region formed via the Sir complex. However, it is unclear whether the histone modifiers that control DNA sequence-independent boundaries function in a chromosome-specific or -nonspecific manner. In this study, we evaluated the effects of the SAGA complex, a histone acetyltransferase (HAT) complex, and its relationship with other histone-modifying enzymes to clarify the mechanism underlying boundary regulation of the IMD2 gene on the right subtelomere of chromosome VIII. We found that Spt8, a component of the SAGA complex, is important for boundary formation in this region and that the inclusion of Spt8 in the SAGA complex is more important than its interaction with TATA-binding protein and TFIIS. In addition to SAGA, various HAT-related factors, such as NuA4 and Rtt109, also functioned in this region. In particular, the SAGA complex induced weak IMD2 expression throughout the cell, whereas NuA4 induced strong expression. These results indicate that multiple HATs contribute to the regulation of boundary formation and IMD2 expression on the right subtelomere of chromosome VIII and that IMD2 expression is determined by the balance between these factors.

Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of p300 using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.

Background: Diapause is an environmentally preprogrammed period of arrested development that is important to insect survival and population growth. Histone acetylation, an epigenetic modification, has several biological functions, but its role in agricultural pest diapause is unknown. In this study, we investigated the role of histone H3 acetylation in the diapause of Helicoverpa armigera., Results: The histone H3 gene of H. armigera was cloned, and multiple sequence alignment of amino acids revealed that the potential lysine acetylation sites were highly conserved across species. Investigation of histone H3 acetylation levels in diapause- and nondiapause-type pupae showed that acetylation levels were down-regulated in diapause-type pupae and were lower in diapausing pupae compared to nondiapause pupae. By screening the genome, six histone acetyltransferase (HAT) and eight histone deacetylase (HDAC) genes responsible for antagonizing catalytic histone acetylation modifications were identified in H. armigera, and most of them exhibited different expression patterns between diapause- and nondiapause-type pupae. To elucidate the effect of histone H3 acetylation on diapause in H. armigera, the diapause pupae were injected with the histone acetylation activator trichostatin A (TSA). The results indicated that TSA injection increased the levels of histone H3 acetylation, causing the diapausing pupae to revert to development. Furthermore, transcriptome analysis revealed that 259 genes were affected by TSA injection, including genes associated with metabolism, resistance, and immunological responses., Conclusion: These results suggest that histone acetylation is inseparably related to the pupal diapause of H. armigera, which promises to be a potential target for pest control. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Histone acetylation affects numerous cellular processes, such as gene transcription, in both plants and animals. However, the posttranslational modification-participated regulatory networks for crop-yield-related traits are largely unexplored. Here, we characterize a regulatory axis for controlling rice grain size and yield, centered on a potent histone acetyltransferase (chromatin modifier) known as HHC4. HHC4 interacts with and forms a ternary complex with adaptor protein ADA2 and transcription factor bZIP23, wherein bZIP23 recruits HHC4 to specific promoters, and ADA2 and HHC4 additively enhance bZIP23 transactivation on target genes. Meanwhile, HHC4 interacts with and is phosphorylated by GSK3-like kinase TGW3. The resultant phosphorylation triggers several functional impairments of the HHC4 ternary complex. In addition, we identify two major phosphorylation sites of HHC4 by TGW3-sites which play an important role in controlling rice grain size. Overall, our findings thus have critical implications for understanding epigenetic basis of grain size control and manipulating the knowledge for higher crop productivity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Adenoviral E1A binding protein p300 (EP300 or p300) and its similar paralog, cyclic-AMP response element binding protein (CBP), are important histone acetyltransferases (HAT) and transcriptional co-activators in epigenetics, participating in numerous cellular pathways including proliferation, differentiation and apoptosis. The overexpression or dysregulation of p300/CBP is closely related to oncology-relevant disease. The inhibition of p300 HAT has been found to be a potential drug target. Berberine has been reported to show anticancer activity and synergistic effect in combination with some of the clinical anticancer drugs via modulation of various pathways. Here, the present study sought to discover more chemotypes of berberine derivatives as p300 HAT inhibitors and to examine the combination of these novel analogues with doxorubicin for the treatment of breast cancer. A series of novel berberine derivatives with modifications of A/B/D rings of berberine have been designed, synthesized and screened. Compound 7b was found to exhibit inhibitory potency against p300 HAT with IC 50 values of 1.51 μM. Western blotting proved that 7b decreased H3K27Ac and interfered with the expression of oncology-relevant protein in MCF-7 cells. Further bioactive evaluation showed that combination of compound 7b with doxorubicin could significantly inhibit tumor growth and invasion in vitro and in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Histone acetylation and mitochondrial function contribute importantly to neural differentiation, which is critically associated with neurodevelopmental disorders such as Down Syndrome (DS). However, whether and how histone acetylation regulates mitochondrial function and further affects neural differentiation has not been well described. In this study, when treated with retinoid acid (RA), the human neuroblastoma SH-SY5Y cell line was used as a neural differentiation model. We found that the acetylation of histone H3, especially H3 lysine 14 acetylation (H3K14ac), and mitochondrial function, including biogenesis and electron transport chain, were enhanced during neural differentiation. Specific inhibition of histone acetyltransferases (HATs) induced neural differentiation deficits, accompanied by downregulation of mitochondrial function. Furthermore, RA receptors (RARs) interacting with HATs were involved in the increased H3K14ac and the enhanced mitochondrial function during the neural differentiation process. Finally, receptor-interacting protein 140 (RIP140), a co-repressor of RARs, was also involved in regulating histone acetylation. RIP140 overexpression inhibited histone acetylation and mediated negative feedback on target genes which are involved in RA signaling. These findings evidenced that when interacting with RARs which had been negatively regulated by RIP140, RA promoted neural differentiation by promoting H3K14ac and enhanced mitochondrial function. This provides a molecular foundation for further investigations into abnormal neural development.

The conserved MYST proteins form the largest family of histone acetyltransferases (HATs) that acetylate lysines within the N-terminal tails of histone, enabling active gene transcription. Here, we have investigated the biological and regulatory functions of the MYST family HAT SasC in the opportunistic human pathogenic fungus Aspergillus fumigatus using a series of genetic, biochemical, pathogenic, and transcriptomic analyses. The deletion (Δ) of sasC results in a drastically reduced colony growth, asexual development, spore germination, response to stresses, and the fungal virulence. Genome-wide expression analyses have revealed that the Δ sasC mutant showed 2402 significant differentially expressed genes: 1147 upregulated and 1255 downregulated. The representative upregulated gene resulting from Δ sasC is hacA , predicted to encode a bZIP transcription factor, whereas the UV-endonuclease UVE-1 was significantly downregulated by Δ sasC . Furthermore, our Western blot analyses suggest that SasC likely catalyzes the acetylation of H3K9, K3K14, and H3K29 in A . fumigatus . In conclusion, SasC is associated with diverse biological processes and can be a potential target for controlling pathogenic fungi.

Background: Histone acetylation is involved in the regulation of stress responses in multiple organisms. Dermacentor silvarum is an important vector tick species widely distributed in China, and low temperature is a crucial factor restricting the development of its population. However, knowledge of the histone acetyltransferases and epigenetic mechanisms underlying cold-stress responses in this tick species is limited., Methods: Histone acetyltransferase genes were characterized in D. silvarum, and their relative expressions were determined using qPCR during cold stress. The association and modulation of histone acetyltransferase genes were further explored using RNA interference, and both the H3K9 acetylation level and relative expression of KAT5 protein were evaluated using western blotting., Results: Three histone acetyltransferase genes were identified and named as DsCREBBP, DsKAT6B, and DsKAT5. Bioinformatics analysis showed that they were unstable hydrophilic proteins, characterized by the conserved structures of CBP (ZnF_TAZ), PHA03247 super family, Creb_binding, and MYST(PLN00104) super family. Fluorescence quantitative PCR showed that the expression of DsCREBBP, DsKAT6B, and DsKAT5 increased after 3 days of cold treatment, with subsequent gradual decreases, and was lowest on day 9. Western blotting showed that both the H3K9 acetylation level and relative expression of KAT5 in D. silvarum increased after treatment at - 4, 4, and 8 °C for 3 and 6 days, whereas they decreased significantly after a 9-day treatment. RNA interference induced significant gene silencing, and the mortality rate of D. silvarum significantly increased at the respective semi-lethal temperatures., Conclusion: These results imply that histone acetyltransferases play an important role in tick adaptation to low temperatures and lay a foundation for further understanding of the epigenetic regulation of histone acetylation in cold-stressed ticks. Further research is needed to elucidate the mechanisms underlying histone acetylation during cold stress in ticks., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC 50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Histone acetyltransferases of the CBP/p300 family are involved in transcriptional regulation and many biological processes (cell proliferation and differentiation, development, and regulation of the stress response and metabolism). Overexpression and knockdown of the nejire (nej) gene (codes for an ortholog of human CBP/p300 proteins) in various tissues (the fat body, intestine, and nervous system) and at various stages of the life cycle (throughout all developmental stages or in adulthood only) were tested for effect on lifespan in the fruit fly Drosophila melanogaster. The activation of nej exerted a positive or a negative effect on the lifespan, depending on the induction mode and the sex. A 6-15% greater lifespan was observed in females with conditional overexpression of nej in the intestine and constitutive overexpression of nej in the nervous system. A decrease (to 44%) or lack of significant changes in lifespan was detected in all other cases observed. In addition, stress response genes (Sod1, Gadd45, Hsp27, Hsp68, and Hif1) were regulated by nej activation. nej knockdown caused a pronounced negative effect on the D. melanogaster lifespan in most variants of the experiment.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.

The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is a transcriptional co-activator that both acetylates and deubiquitinates histones. The histone acetyltransferase (HAT) subunit, Gcn5, is part of a subcomplex of SAGA called the HAT module. A minimal HAT module complex containing Gcn5 bound to Ada2 and Ada3 is required for full Gcn5 activity on nucleosomes. Deletion studies have suggested that the Ada2 SWIRM domain plays a role in tethering the HAT module to the remainder of SAGA. While recent cryo-EM studies have resolved the structure of the core of the SAGA complex, the HAT module subunits and molecular details of its interactions with the SAGA core could not be resolved. Here we show that the SWIRM domain is required for incorporation of the HAT module into the yeast SAGA complex, but not the ADA complex, a distinct six-protein acetyltransferase complex that includes the SAGA HAT module proteins. In the isolated Gcn5/Ada2/Ada3 HAT module, deletion of the SWIRM domain modestly increased activity but had negligible effect on nucleosome binding. Loss of the HAT module due to deletion of the SWIRM domain decreases the H2B deubiquitinating activity of SAGA, indicating a role for the HAT module in regulating SAGA DUB module activity. A model of the HAT module created with Alphafold Multimer provides insights into the structural basis for our biochemical data, as well as prior deletion studies., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Histone acetylation is one of the most pivotal epigenetic mechanisms in eukaryotes and has been tightly linked to the regulation of various genes controlling growth, development and response to environmental stresses in both animals and plants. Till date, the association of histone acetylation to dehydration stress in red algae and genes encoding the enzymes responsible for histone acetylation: histone acetyltransferases (HATs) or histone deacetylases (HDACs), remains largely unknown. In this study, in silico analysis of the red seaweed Pyropia yezoensis identified 6 HAT genes and 10 HDAC genes. These genes displayed good synteny in genome loci with their Pyropia haitanensis orthologs except for a putative gene duplication event in HDAC and a loss of one HAT gene in P. yezoensis . According to the conserved domains and phylogenetic analysis, they encoded three GCNA5-, one TAFII250- and one MYST-HAT, as well as five HDA1-and five SIRT-HDACs. The sirtuin-domain of Py06502 harbored a ~100 aa insert and interestingly, this insertion was specifically observed in Bangiales species. Two nuclear-localized HATs were transcriptionally up-regulated at the early stage of dehydration and so were two nuclear HDA1s when moderate dehydration started, suggesting their potential roles in modulating downstream gene expression to facilitate dehydration adaptation by changing histone acetylation patterns on relevant regulatory elements. This was experimentally confirmed by the increased decline in photosynthesis efficiency during dehydration when HAT and HDAC activities were inhibited by SAHA and MB-3, respectively. Transcriptional patterns of multiple dehydration-responsive genes after water loss were strongly affected by MB-3 or SAHA treatment. This study provides the first insight into the regulation and function of HAT/HDAC during stress adaptation in red algae., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Qian, Wang, Pang, Guan, Poetsch and Wang.)

Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase (HAT) complex may be involved in regulating YY1 transcriptional activity; however, the precise interaction between MOF-HAT and YY1, as well as whether the acetylation activity of MOF impacts the function of YY1, has not been reported. Here, we present evidence that the MOF-containing male-specific lethal (MSL) HAT complex regulates YY1 stability and transcriptional activity in an acetylation-dependent manner. First, the MOF/MSL HAT complex was bound to and acetylated YY1, and this acetylation further promoted the ubiquitin-proteasome degradation pathway of YY1. The MOF-mediated degradation of YY1 was mainly related to the 146-270 amino acid residues of YY1. Further research clarified that acetylation-mediated ubiquitin degradation of YY1 mainly occurred through lysine 183. A mutation at the YY1K183 site was sufficient to alter the expression level of p53-mediated downstream target genes, such as CDKN1A (encoding p21), and it also suppressed the transactivation of YY1 on CDC6 . Furthermore, a YY1K183R mutant and MOF remarkably antagonized the clone-forming ability of HCT116 and SW480 cells facilitated by YY1, suggesting that the acetylation-ubiquitin mode of YY1 plays an important role in tumor cell proliferation. These data may provide new strategies for the development of therapeutic drugs for tumors with high expression of YY1.

Hypertrophic stress-induced cardiac remodeling is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. Continuation of this response eventually leads to heart failure. The histone acetyltransferase p300 plays an important role in the development of heart failure, and may be a target for heart failure therapy. The phenolic phytochemical 6-shogaol, a pungent component of raw ginger, has various bioactive effects; however, its effect on cardiovascular diseases has not been investigated. One micromolar of 6-shogaol suppressed phenylephrine (PE)-induced increases in cardiomyocyte hypertrophy in rat primary cultured cardiomyocytes. In rat primary cultured cardiac fibroblasts, 6-shogaol suppressed transforming growth factor-beta (TGF-β)-induced increases in L-proline incorporation. It also blocked PE- and TGF-β-induced increases in histone H3K9 acetylation in the same cells and in vitro. An in vitro p300-HAT assay revealed that 6-shogaol suppressed histone acetylation. The mice underwent transverse aortic constriction (TAC) surgery, and were administered 0.2 or 1 mg/kg of 6-shogaol daily for 8 weeks. 6-shogaol prevented TAC-induced systolic dysfunction and cardiac hypertrophy in a dose-dependent manner. Furthermore, it also significantly inhibited TAC-induced increases in histone H3K9 acetylation. These results suggest that 6-shogaol may ameliorate heart failure through a variety of mechanisms, including the inhibition of p300-HAT activity.

Background: Histone acetyltransferases (HATs) play an important role in plant growth and development, stress response, and regulation of secondary metabolite biosynthesis. Hemp (Cannabis sativa L.) is famous for its high industrial, nutritional, and medicinal value. It contains non-psychoactive cannabinoid cannabidiol (CBD) and cannabinol (CBG), which play important roles as anti-inflammatory and anti-anxiety. At present, the involvement of HATs in the regulation of cannabinoid CBD and CBG synthesis has not been clarified., Methods: The members of HAT genes family in hemp were systematically analyzed by bioinformatics analysis. In addition, the expression level of HATs and the level of histone acetylation modification were analyzed based on transcriptome data and protein modification data. Real-time quantitative PCR was used to verify the changes in gene expression levels after inhibitor treatment. The changes of CBD and CBG contents after inhibitor treatment were verified by HPLC-MS analysis., Results: Here, 11 HAT genes were identified in the hemp genome. Phylogenetic analysis showed that hemp HAT family genes can be divided into six groups. Cannabinoid synthesis genes exhibited spatiotemporal specificity, and histones were acetylated in different inflorescence developmental stages. The expression of cannabinoid synthesis genes was inhibited and the content of CBD and CBG declined by 10% to 55% in the samples treated by HAT inhibitor (PU139). Results indicated that CsHAT genes may regulate cannabinoid synthesis through altering histone acetylation., Conclusions: Our study provides genetic information of HATs responsible for cannabinoid synthesis, and offers a new approach for increasing the content of cannabinoid in hemp., (© 2023. The Author(s).)

In this study, a checkerboard arranged G4 nanostructure-supported electrochemical platform is developed well for the application to unique bio-enzymes examination. Herein, we focus on the two bio-enzymes involving histone acetyltransferase (HAT) and terminal deoxynucleotidyl transferase (TdT); the former leads to the acetyl transfer of acetyl coenzyme A to the lysine residue of the substrate peptide and the latter achieves the polymeric extension of DNA without template under a unique pool of dATP and dGTP (4: 6). A complex of antibody and short DNA is introduced onto the electrode surface based on the affinity interaction between acetyl in acetylated peptide and its antibody. and used for initiating reaction. Then, TdT-yielded rich-G sequence is formed to act as the backbone of checkerboard, and subsequently free G-DNAs can be stacked continually on the backbone under Mg 2+ . An excellent electrocatalytic signal to H 2 O 2 emerges noticeably, which is related with the activity of HAT p300 and TdT with a low detection limit of 2.3 pM and 0.38 mU/mL, respectively. Finally, this strategy is also used successfully for the inhibitor screening and complex sample analysis, which has important implications for the advancement of HAT- and TdT-related electrochemical bioassay and drug discovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cassava bacterial blight (CBB) is one of the most serious diseases in cassava production, so it is essential to explore the underlying mechanism of immune responses. Histone acetylation is an important epigenetic modification, however, its relationship with cassava disease resistance remains unclear. Here, we identified 10 histone acetyltransferases in cassava and found that the transcript of MeHAM1 showed the highest induction to CBB. Functional analysis showed that MeHAM1 positively regulated disease resistance to CBB through modulation of salicylic acid (SA) accumulation. Further investigation revealed that MeHAM1 directly activated SA biosynthetic genes' expression via promoting lysine 9 of histone 3 (H3K9) acetylation and lysine 5 of histone 4 (H4K5) acetylation of these genes. In addition, molecular chaperone MeDNAJA2 physically interacted with MeHAM1, and MeDNAJA2 also regulated plant immune responses and SA biosynthetic genes. In conclusion, this study illustrates that MeHAM1 and MeDNAJA2 confer immune responses through transcriptional programming of SA biosynthetic genes via histone acetylation. The MeHAM1 & MeDNAJA2-SA biosynthesis module not only constructs the direct relationship between histone acetylation and cassava disease resistance, but also provides gene network with potential value for genetic improvement of cassava disease resistance., (© 2022 John Wiley & Sons Ltd.)

Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a pivotal role in the regulation of gene expression and diverse biological processes. However, the function of GNAT family HATs, especially Elp3, in the opportunistic human pathogenic fungus Aspergillus fumigatus is largely unknown. To investigate the roles of the GNAT family HATs Elp3 and GcnE in the A. fumigatus , we have generated and characterized individual null Δ elp3 and Δ gcnE mutants. The radial growth of fungal colonies was significantly decreased by the loss of elp3 or gcnE , and the number of asexual spores (conidia) in the Δ gcnE mutant was significantly reduced. Moreover, the mRNA levels of the key asexual development regulators were also significantly low in the Δ gcnE mutant compared to wild type (WT). Whereas both the Δ elp3 and Δ gcnE mutants were markedly impaired in the formation of adherent biofilms, the Δ gcnE mutant showed a complete loss of surface structure and of intercellular matrix. The Δ gcnE mutant responded differently to oxidative stressors and showed significant susceptibility to triazole antifungal agents. Furthermore, Elp3 and GcnE function oppositely in the production of secondary metabolites, and the Δ gcnE mutant showed attenuated virulence. In conclusion, Elp3 and GcnE are associated with diverse biological processes and can be potential targets for controlling the pathogenic fungus.

Helicobacter pylori infection is one of the leading factors that promotes, among other diseases, gastric cancer (GC). Infection of gastric epithelial cells (GECs) by H. pylori enhances the expression as well as acetylation of the E3 ubiquitin ligase SIAH2 which promotes GC progression. The histone acetyltransferase (HAT) activity of p300 catalyzes SIAH2 acetylation following H. pylori infection. Since reactive oxygen species (ROS) generation in H. pylori-infected GECs accelerates GC progression, acetylation-mediated SIAH2 regulation might be a crucial modifier of ROS generation in the infected GECs. Here, we describe a compendium of methods to evaluate the effects of HAT/lysine acetyl transferase (KAT) inhibitors (HAT/KATi) on SIAH2-mediated ROS regulation in H. pylori-infected GECs., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Estrogen accounts for several biological processes in the body; embryo implantation and pregnancy being one of the vital events. This manuscript aims to unearth the nuclear role of Son of sevenless1 (SOS1), its interaction with estrogen receptor alpha (ERα), and signal transducer and activator of transcription 3 (STAT3) in the uterine nucleus during embryo implantation. SOS1, a critical cytoplasmic linker between receptor tyrosine kinase and rat sarcoma virus signaling, translocates into the nucleus via its bipartite nuclear localization signal (NLS) during the 'window of implantation' in pregnant mice. SOS1 associates with chromatin, interacts with histones, and shows intrinsic histone acetyltransferase (HAT) activity specifically acetylating lysine 16 (K16) residue of histone H4. SOS1 is a coactivator of STAT3 and a co-repressor of ERα. SOS1 creates a partial mesenchymal-epithelial transition by acting as a transcriptional modulator. Finally, our phylogenetic tree reveals that the two bipartite NLS surface in reptiles and the second acetyl coenzymeA (CoA) (RDNGPG) important for HAT activity emerges in mammals. Thus, SOS1 has evolved into a moonlighting protein, the special class of multi-tasking proteins, by virtue of its newly identified nuclear functions in addition to its previously known cytoplasmic function.

Homeostasis in the blood system is maintained by the balance between self-renewing stem cells and nonstem cells. To promote self-renewal, transcriptional regulators maintain epigenetic information during multiple rounds of cell division. Mutations in such transcriptional regulators cause aberrant self-renewal, leading to leukemia. MOZ, a histone acetyltransferase, and MLL, a histone methyltransferase, are transcriptional regulators that promote the self-renewal of hematopoietic stem cells. Gene rearrangements of MOZ and MLL generate chimeric genes encoding fusion proteins that function as constitutively active forms. These MOZ and MLL fusion proteins constitutively activate transcription of their target genes and cause aberrant self-renewal in committed hematopoietic progenitors, which normally do not self-renew. Recent progress in the field suggests that MOZ and MLL are part of a transcriptional activation system that activates the transcription of genes with nonmethylated CpG-rich promoters. The nonmethylated state of CpGs is normally maintained during cell divisions from the mother cell to the daughter cells. Thus, the MOZ/MLL-mediated transcriptional activation system replicates the expression profile of mother cells in daughter cells by activating the transcription of genes previously transcribed in the mother cell. This review summarizes the functions of the components of the MOZ/MLL-mediated transcriptional activation system and their roles in the promotion of self-renewal., (© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Nucleosome acetyltransferase of H4 (NuA4), one of two major histone acetyltransferase complexes in Saccharomyces cerevisiae  specifically acetylates histone H2A and H4, resulting in increased transcriptional activity. Here we present a 3.8-4.0 Å resolution structure of the NuA4 complex from cryoelectron microscopy and associated biochemical studies. The determined structure comprises six subunits and appropriately 5,000 amino acids, with a backbone formed by subunits Eaf1 and Eaf2 spanning from an Actin-Arp4 module to a platform subunit Tra1. Seven subunits are missing from the cryo-EM map. The locations of missing components, Yaf9, and three subunits of the Piccolo module Esa1, Yng2, and Eaf6 were determined. Biochemical studies showed that the Piccolo module and the complete NuA4 exhibit comparable histone acetyltransferase activities, but the Piccolo module binds to nucleosomes, whereas the complete NuA4 does not. The interaction lifetime of NuA4 and nucleosome is evidently short, possibly because of subunits of the NuA4 complex that diminish the affinity of the Piccolo module for the nucleosome, enabling rapid movement from nucleosome to nucleosome.

In eukaryotes, CREB-binding protein (CBP), a coactivator of CREB, functions both as a platform for recruiting other components of the transcriptional machinery and as a histone acetyltransferase (HAT) that alters chromatin structure. We previously showed that the transcriptional activity of cAMP-responsive element binding protein (CREB) plays a crucial role in neuronal plasticity in the pond snail Lymnaea stagnalis. However, there is no information on the molecular structure and HAT activity of CBP in the Lymnaea central nervous system (CNS), hindering an investigation of its postulated role in long-term memory (LTM). Here, we characterize the Lymnaea CBP (LymCBP) gene and identify a conserved domain of LymCBP as a functional HAT. Like CBPs of other species, LymCBP possesses functional domains, such as the KIX domain, which is essential for interaction with CREB and was shown to regulate LTM. In-situ hybridization showed that the staining patterns of LymCBP mRNA in CNS are very similar to those of Lymnaea CREB1. A particularly strong LymCBP mRNA signal was observed in the cerebral giant cell (CGC), an identified extrinsic modulatory interneuron of the feeding circuit, the key to both appetitive and aversive LTM for taste. Biochemical experiments using the recombinant protein of the LymCBP HAT domain showed that its enzymatic activity was blocked by classical HAT inhibitors. Preincubation of the CNS with such inhibitors blocked cAMP-induced synaptic facilitation between the CGC and an identified follower motoneuron of the feeding system. Taken together, our findings suggest a role for the HAT activity of LymCBP in synaptic plasticity in the feeding circuitry., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

α-synuclein (αS) is a β-sheet intracellular protein that has been implicated as a major pathological hallmark of Parkinson's disease (PD). Several studies have shown that overexpression of αS causes dopaminergic cell loss; however, the role of αS in apoptosis remains not fully known. Therefore, this study aims to address the mechanisms of the αS overexpression model in apoptosis and to its correlation with PD pathogenesis. Here, we used a human αS (hαS) plasmid to characterize the role of ectopic αS in neuronal apoptosis in sporadic PD in vitro . We found that overexpression of αS transcriptionally upregulated Bim-mediated apoptosis in neuronal SH-SY5Y cells. Interestingly, αS overexpression inhibited general control non-depressible 5 (GCN5), a histone acetyltransferase (HAT), and promoted transcriptional upregulation of Bim. Consequently, co-overexpression of GCN5 in the αS overexpressed model showed a reversal of αS toxicity in neuronal cells. These in vitro findings support the hypothesis of αS-mediated histone deacetylation and dopaminergic neuronal loss in PD. Moreover, our study indicates that therapeutic activation/homeostasis of GCN5 may benefit PD and other α-synucleinopathies.

Camellia oleifera is a woody edible-oil plant in China, and anthracnose occurs wherever it is grown, causing serious losses each year. We previously identified that the histone acetyltransferase CfGcn5 orchestrates growth, development, and pathogenicity in Colletotrichum fructicola , the major causal agent of anthracnose on C. oleifera . To elucidate the underlying mechanism, we conducted a transcriptome analysis and found that CfGcn5 is mainly involved in ribosomes, catalytic and metabolic processes, primary metabolism, and autophagy. In addition, we provided evidence showing that CfGcn5 serves as an autophagy repressor to mediate the expression of many autophagy-related genes ( ATG ) and undergoes degradation during autophagy. Moreover, we found that the CfATG8 and CfATG9 gene-deletion mutants had defects in mitosis and autophagy, resulting in their decreased appressoria formation rates and lower turgor pressure. These combined effects caused the failure of their appressoria functions and caused defects on their pathogenicity, revealing the importance of autophagy in pathogenicity. Taken together, our study illustrates that the autophagy repressor CfGcn5 undergoes degradation in order to regulate autophagy-dependent pathogenicity in C. fructicola . IMPORTANCE Colletotrichum spp. is ranked in the top 10 plant fungal pathogens and serves as a model for the study of hemibiotrophic pathogens, but its molecular mechanisms of pathogenesis remain largely unknown. Among species of Colletotrichum , C. fructicola . We previously identified that the histone acetyltransferase CfGcn5 regulates growth, development, and pathogenicity in Camellia oleifera . We previously identified that the histone acetyltransferase CfGcn5 regulates growth, development, and pathogenicity in C. fructicola . To explore the underlying mechanisms, we performed comparative transcriptomic studies and found that CfGcn5 regulates global gene expression, including multiple autophagy-related genes ( ATG genes). We revealed that CfGcn5 is an autophagy repressor that undergoes degradation during autophagy to govern pathogenicity. We also showed that the autophagy-related proteins CfAtg8 and CfAtg9 are required for full pathogenicity due to their regulatory functions in mitosis and autophagy. Our findings are important because we provide the first comprehensive characterization of autophagy as well as the relationship between acetylation and autophagy functioning in the pathogenesis of Colletotrichum spp., which might offer new potential targets for the management of anthracnose disease.

The methylotrophic yeast Komagataella phaffii ( a.k.a. Pichia pastoris ) harbors a methanol utilization (MUT) pathway, enabling it to utilize methanol as the sole source of carbon. The nexus between transcription factors such as Mxr1p and Trm1p and chromatin-modifying enzymes in the regulation of genes of MUT pathway has not been well studied in K. phaffii . Using transcriptomics, we demonstrate that Gcn5, a histone acetyltransferase, and Gal83, one of the beta subunits of nuclear-localized SNF1 (sucrose non-fermenting 1) kinase complex are essential for the transcriptional regulation by the zinc finger transcription factors Mxr1p and Trm1p. We conclude that interactions among Gcn5, Snf1, Mxr1p, and Trm1p play a critical role in the transcriptional regulation of genes of MUT pathway of K. phaffii ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gupta and Rangarajan.)

Invertase (INV)-mediated sucrose (Suc) hydrolysis, leading to the irreversible production of glucose (Glc) and fructose (Frc), plays an essential role in abiotic stress tolerance of plants. However, the regulatory network associated with the Suc catabolism in response to cold environment remains largely elusive. Herein, the cold-induced alkaline/neutral INV gene PtrA/NINV7 of trifoliate orange (Poncirus trifoliata (L.) Raf.) was shown to function in cold tolerance via mediating the Suc hydrolysis. Meanwhile, a nuclear matrix-associated region containing A/T-rich sequences within its promoter was indispensable for the cold induction of PtrA/NINV7. Two AT-Hook Motif Containing Nuclear Localized (AHL) proteins, PtrAHL14 and PtrAHL17, were identified as upstream transcriptional activators of PtrA/NINV7 by interacting with the A/T-rich motifs. PtrAHL14 and PtrAHL17 function positively in the cold tolerance by modulating PtrA/NINV7-mediated Suc catabolism. Furthermore, both PtrAHL14 and PtrAHL17 could form homo- and heterodimers between each other, and interacted with two histone acetyltransferases (HATs), GCN5 and TAF1, leading to elevated histone3 acetylation level under the cold stress. Taken together, our findings unraveled a new cold-responsive signaling module (AHL14/17-HATs-A/NINV7) for orchestration of Suc catabolism and cold tolerance, which shed light on the molecular mechanisms underlying Suc catabolism catalyzed by A/NINVs under cold stress., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

In eukaryotic cells, loosening of chromatin causes changes in transcription and DNA replication. The artificial conversion of tightly packed chromatin (heterochromatin) to loosely packed chromatin (euchromatin) enables gene expression and regulates cell differentiation. Although some chemicals convert chromatin structures through histone modifications, they lack sequence specificity. This study attempted to establish a novel technology for inducing chromatin loosening in target regions of Saccharomyces cerevisiae . We focused on histone acetylation, which is one of the mechanisms of euchromatin induction. The sequence-recognizing ability of the dead Cas9 (dCas9) and guide RNA (gRNA) complex was used to promote histone acetylation at a targeted genomic locus. We constructed a plasmid to produce a fusion protein consisting of dCas9 and histone acetyltransferase Gcn5 and a plasmid to express gRNA recognizing the upstream region of heterochromatic URA3 . Confocal microscopy revealed that the fusion proteins were localized in the nucleus. The yeast strain producing the fusion protein and gRNA grew well in the uracil-deficient medium, while the strain harboring empty plasmids or the strain containing the mutations that cause loss of nucleosomal histone acetylation activity of Gcn5 did not. This suggests that the heterochromatin was loosened as much as euchromatin through nucleosomal histone acetylation. The amount of euchromatic DNA at the target locus increased, indicating that chromatin loosening was induced by our system. Nucleosomal histone acetylation in heterochromatic loci by our developed system is a promising method for inducing euchromatic state in a target locus.

Transcriptional activity is mediated by chromatin remodeling, which in turn is affected by post-translational modifications, including histone acetylation. Histone acetyltransferases (HATs) are capable of promoting euchromatin formation and then activating gene transcription. Here, we characterize the Elp3 GNAT family HAT, which is also a subunit of Elongator complex, in the environmentally and economically important fungal insect pathogen, Beauveria bassiana. BbElp3 showed high localization levels to mitochondria, with some nuclear and cytoplasmic localization also apparent. Targeted gene knockout of BbElp3 resulted in impaired asexual development and morphogenesis, reduced tolerances to multiple stress conditions, reduced the ability of the fungus to utilize various carbon/nitrogen sources, increased susceptibility to rapamycin, and attenuated virulence in bioassays using the greater wax moth, Galleria mellonella . The Δ BbElp3 mutant also showed disrupted cell cycle, abnormal hyphal septation patterns, and enlarged autophagosomes in vegetative hyphae. Transcriptome analyses revealed differential expression of 775 genes (DEGs), including 336 downregulated and 438 upregulated genes in the Δ BbElp3 strain as compared to the wild type. Downregulated genes were mainly enriched in pathways involved in DNA processing and transcription, cell cycle control, cellular transportation, cell defense, and virulence, including hydrophobins, cellular transporters (ABC and MFS multidrug transporters), and insect cuticular degrading enzymes, while upregulated genes were mainly enriched in carbohydrate metabolism and amino acid metabolism. These data indicate pleiotropic effects of BbElp3 in impacting specific cellular processes related to asexual development, cell cycle, autophagy, and virulence.

Epigenetic changes associated with histone modifications play an important role in the emergence and maintenance of the phenotype of various cancer types. In contrast to direct mutations in the main DNA sequence, these changes are reversible, which makes the development of inhibitors of enzymes of post-translational histone modifications one of the most promising strategies for the creation of anticancer drugs. To date, a wide variety of histone modifications have been found that play an important role in the regulation of chromatin state, gene expression, and other nuclear events. This review examines the main features of the most common and studied epigenetic histone modifications with a proven role in the pathogenesis of a wide range of malignant neoplasms: acetylation / deacetylation and methylation / demethylation of histone proteins, as well as the role of enzymes of the HAT / HDAC and HMT / HDMT families in the development of oncological pathologies. The data on the relationship between histone modifications and certain types of cancer are presented and discussed. Special attention is devoted to the consideration of various strategies for the development of epigenetic inhibitors. The main directions of the development of inhibitors of histone modifications are analyzed and effective strategies for their creation are identified and discussed. The most promising strategy is the use of multitarget drugs, which will affect multiple molecular targets of cancer. A critical analysis of the current status of approved epigenetic anticancer drugs has also been performed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC 50 s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on other classes of HATs in human. Compound 29 inhibited cellular acetylation of several histone lysine residues and showed strong activity against proliferation of a panel of solid and blood cancer cells. These results indicate it is a novel pharmacological lead for drug development targeting these cancers as well as a useful chemical probe for biological studies of p300/CBP., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Histone acetyltransferases (HATs, also known as lysine acetyltransferases, KATs) catalyze acetylation of their cognate protein substrates using acetyl-CoA (Ac-CoA) as a cofactor and are involved in various physiological and pathological processes. Advances in mass spectrometry-based proteomics have allowed the discovery of thousands of acetylated proteins and the specific acetylated lysine sites. However, due to the rapid dynamics and functional redundancy of HAT activities, and the limitation of using antibodies to capture acetylated lysines, it is challenging to systematically and precisely define both the substrates and sites directly acetylated by a given HAT. Here, we describe a chemoproteomic approach to identify and profile protein substrates of individual HAT enzymes on the proteomic scale. The approach involves protein engineering to enlarge the Ac-CoA binding pocket of the HAT of interest, such that a mutant form is generated that can use functionalized acyl-CoAs as a cofactor surrogate to bioorthogonally label its protein substrates. The acylated protein substrates can then be chemoselectively conjugated either with a fluorescent probe (for imaging detection) or with a biotin handle (for streptavidin pulldown and chemoproteomic identification). This modular chemical biology approach has been successfully implemented to identify protein substrates of p300, GCN5, and HAT1, and it is expected that this method can be applied to profile and identify the sub-acetylomes of many other HAT enzymes. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Labeling HAT protein substrates with azide/alkyne-biotin Alternate Protocol: Labeling protein substrates of HATs with azide/alkyne-TAMRA for in-gel visualization Support Protocol 1: Expression and purification of HAT mutants Support Protocol 2: Synthesis of Ac-CoA surrogates Basic Protocol 2: Streptavidin enrichment of biotinylated HAT substrates Basic Protocol 3: Chemoproteomic identification of HAT substrates Basic Protocol 4: Validation of specific HAT substrates with western blotting., (© 2022 Wiley Periodicals LLC.)

The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure-activity relationship studies on cardiomyocyte hypertrophy using CUR have been conducted. To evaluate if prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) can suppress cardiomyocyte hypertrophy, cultured cardiomyocytes were treated with CUR, PPC, or PyrC and then stimulated with phenylephrine (PE). PE-induced cardiomyocyte hypertrophy was inhibited by PyrC but not PPC at a lower concentration than CUR. Western blotting showed that PyrC suppressed PE-induced histone acetylation. However, an in vitro HAT assay showed that PyrC did not directly inhibit p300-HAT activity. As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. Phosphorylation of p300 by Cdk9 was suppressed by PyrC. Immunoprecipitation-WB showed that PyrC inhibits Cdk9 binding to CyclinT1 in cultured cardiomyocytes. PyrC may prevent cardiomyocyte hypertrophic responses by indirectly suppressing both p300-HAT activity and RNA polymerase II transcription elongation activity via inhibition of Cdk9 kinase activity.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Aberrant histone acetylation is increasingly thought to play important roles in the pathogenesis of autoimmune diseases. However, there are very few data on histone acetylation in primary Sjögren's syndrome (pSS). We aimed to investigate whether there was abnormal histones acetylation in patients with pSS., Methods: We investigated the expressions of histone acetyltransferase (HAT) genes (p300, CREBBP and PCAF) by real-time PCR in the peripheral blood mononuclear cells (PBMCs) of pSS patients. HAT activity and histone H3/H4 acetylation activity were measured by activity kit, and histone H3/H4 acetylation was verified by Western blot (WB). Spearman test was utilized to analyze the association between HAT activity levels and clinical parameters of pSS patients., Results: The mRNA expressions of p300, CREBBP and PCAF in PBMCs from pSS patients were decreased in comparison with healthy controls (P < 0.05). HAT activity and histone H3/H4 acetylation were reduced in PBMCs from pSS patients (P < 0.05). We found that HAT activity was negatively correlated with CRP (P = 0.040) and TNF-α (P = 0.012), and was positively correlated with C4 (P = 0.041)., Conclusions: Histone hypoacetylation is observed in patients with pSS and is involved in the pathogenesis of pSS., Key Points: • The mRNA expressions of p300, CREBBP and PCAF in PBMCs from pSS patients were decreased in comparison with HCs. • HAT activity and histone H3/H4 acetylation were reduced in PBMCs from pSS patients. • HAT activity was correlated with disease characters. • We show for the first time that the histone hypoacetylation may be involved in the pathogenesis of pSS., (© 2021. International League of Associations for Rheumatology (ILAR).)