Search

Background: The physiopathology of sarcopenia shares common biological cascades with the aging process, as does any other age-related condition. However, our understanding of the interconnected pathways between diagnosed sarcopenia and aging remains limited, lacking sufficient scientific evidence., Methods: This narrative review aims to gather and describe the current evidence on the relationship between biological aging determinants, commonly referred to as the hallmarks of aging, and diagnosed sarcopenia in humans., Results: Among the twelve hallmarks of aging studied, there appears to be a substantial association between sarcopenia and mitochondrial dysfunction, epigenetic alterations, deregulated nutrient sensing, and altered intercellular communication. Although limited, preliminary evidence suggests a promising association between sarcopenia and genomic instability or stem cell exhaustion., Discussion: Overall, an imbalance in energy regulation, characterized by impaired mitochondrial energy production and alterations in circulatory markers, is commonly associated with sarcopenia and may reflect the interplay between aging physiology and sarcopenia biology., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Epitranscriptomic regulation of cell functions involves multiple post-transcriptional chemical modifications of coding and non-coding RNA that are increasingly recognized in studying human brain disorders. Although rodent models are presently widely used in neuroepitranscriptomic research, the zebrafish (Danio rerio) has emerged as a useful and promising alternative model species. Mounting evidence supports the importance of RNA modifications in zebrafish CNS function, providing additional insights into epitranscriptomic mechanisms underlying a wide range of brain disorders. Here, we discuss recent data on the role of RNA modifications in CNS regulation, with a particular focus on zebrafish models, as well as evaluate current problems, challenges, and future directions of research in this field of molecular neurochemistry., (© 2025 International Society for Neurochemistry.)

Early environmental exposures can have long-term effects on child's development and health. Epigenetic modifications may partly explain these effects, and studying them could lead to significant advances in our understanding of the underlying mechanisms. This review summarises recent data on epigenetic and environmental epidemiology during the first 1000 days of life for several common exposures, including tobacco, phenols and phthalates, air pollutants, ambient temperature and vegetation., (© 2024 médecine/sciences – Inserm.)

The development of sequencing technologies and their increased accessibility in clinical services and genetic laboratories have considerably accelerated the identification of genetic variants associated with rare diseases (RDs). Among these, Mendelian disorders of the epigenetic machinery (MDEM) are rare monogenic diseases characterized by the presence of mutations in genes encoding epigenetic regulators that play a key role in organismal development and cellular functions. Loss of function of these regulators is expected to lead to epigenetic modifications that profoundly affect genome expression and cellular identity. Disruptions in DNA methylation profiles have been documented in MDEMs, emerging as a useful diagnostic tool. The current challenge is to determine whether and how these epigenomic alterations drive the mechanisms underlying the clinical manifestations in patients suffering from this class of diseases. Studying MDEMs may therefore shed light on the important role of epigenetic information in health and disease, particularly the mechanisms involved in the development and understanding of complex pathologies, such as neurodevelopmental disorders and cancer., (© 2024 médecine/sciences – Inserm.)

The memory of cellular identity is crucial for the correct development of an individual and is maintained throughout life by the epigenome. Chromatin marks, such as DNA methylation and histone modifications, ensure the stability of gene expression programmes over time and through cell division. Loss of these marks can lead to severe pathologies, including cancer and developmental syndromes. However, reprogramming of cellular identity is also a natural phenomenon that occurs early in mammalian development, particularly in the germ line, which enables the production of mature and functional gametes. The germ line transmits genetic and epigenetic information to the next generation, contributing to the survival of the species. Primordial germ cells (PGCs) undergo extensive chromatin remodelling, including global DNA demethylation and erasure of the parental imprints. This review introduces the concept of epigenetic reprogramming, its discovery and key steps, as well as the transcriptional and chromatin changes that accompany germ cell formation in mice. Finally, we discuss the epigenetic mechanisms of genomic imprinting, its discovery, regulation and relevance to human disease., (© 2024 médecine/sciences – Inserm.)

Cellular differentiation and homeostasis rely on complex mechanisms to control gene expression, enabling the different cell lineages of an organism to establish and then "memorize" different epigenetic states. The processes that control gene expression are centered on chromatin, a complex of DNA, histone proteins and RNA, whose structure is finely regulated. Targeted epigenomic engineering tools make it possible to interfere with and study these processes, revealing the logic of epigenetic memory mechanisms. This article reviews the main classes of targeted epigenome modification tools and illustrates how they can be used to better understand and modify the epigenome of cells, paving the way for potentially revolutionary therapeutic prospects., (© 2024 médecine/sciences – Inserm.)

Alterations in DNA methylation profiles are typically found in cancer cells, combining genome-wide hypomethylation with hypermethylation of specific regions, such as CpG islands, which are normally unmethylated. Driving effects in cancer development have been associated with alteration of DNA methylation in certain regions, inducing, for example, the repression of tumor suppressor genes or the activation of oncogenes and retrotransposons. These alterations represent prime candidates for the development of specific markers for the detection, diagnosis and prognosis of cancer. In particular, these markers, distributed along the genome, provide a wealth of information that offers potential for innovation in the field of liquid biopsy, in particular thanks to the emergence of artificial intelligence for diagnostic purposes. This could overcome the limitations related to sensitivities and specificities, which remain too low for the most difficult applications in oncology: the detection of cancers at an early stage, the monitoring of residual disease and the analysis of brain tumors. In addition, targeting the enzymatic processes that control the epigenome offers new therapeutic strategies that could reverse the regulatory anomalies of these altered epigenomes., (© 2024 médecine/sciences – Inserm.)

Psychiatric disorders are multifactorial conditions without clear biomarkers, influenced by genetic, environmental, and developmental factors. Understanding these disorders requires identifying specific endophenotypes that help break down their complexity. Here, we undertake an in-depth analysis of one such endophenotype, namely imbalanced approach-avoidance conflict (AAC), reviewing its significant dependency on the hippocampus. Imbalanced AAC is a transdiagnostic endophenotype, being a feature of many psychiatric conditions in humans. However, it is predominantly examined in preclinical research through paradigms that subject rodents to conflict-laden scenarios. This review offers an original perspective by discussing the AAC through three distinct lights: optogenetic modulation of the AAC, which updates our understanding of the hippocampal contribution to behavioral inhibition; the impact of environmental stress, which exacerbates conflict and strengthens the stress-psychopathology axis; and inherent epigenetic aspects, which uncover crucial molecular underpinnings of environmental (mal) adaptation. By integrating these perspectives, in this review we aim to underline a cross-species causal nexus between heightened hippocampal activity and avoidance behavior. In addition, we suggest a rationale to explore epigenetic pharmacology as a potential strategy to tackle AAC-related psychopathology. This review assumes greater significance when viewed through the lens of advancing AAC-centric diagnostics in human subjects. Unlike traditional questionnaires, which struggle to accurately measure individual differences in AAC-related dimensions, new approaches using virtual reality and computer games show promise in better focusing the magnitude of AAC contribution to psychopathology., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

Even today, 'epigenetics' is a rather difficult field to define. The explosive growth of epigenetics over the last twenty years is sometimes seen as a revolutionary event in the life sciences, a paradigm shift that would devalue genetics or the standard view of the evolutionary synthesis. The aim of this paper is to place this controversial issue in its historical context. Building on the excellent work of David Haig, I will show that in the late 1950s, the modern concept of epigenetics emerged as an extension of the nascent theory of molecular biology. Given that genetic information was assimilated to the DNA sequence, and that each cell of an organism was supposed to possess a complete genome, it was thought that certain as yet undiscovered molecular mechanisms were necessary to regulate gene expression. These hypothetical "epigenetic systems", which would not modify the DNA sequence, should also have heritable effect on gene expression, which would explain the stability of cell differentiation during embryogenesis., (© 2024 médecine/sciences – Inserm.)

Epigenetic processes play a crucial role in mediating the impact of environmental energetic challenges, from overconsumption to starvation. Over-nutrition of energy-dense foods and sedentary lifestyles contribute to the development of obesity, characterized by excessive fat storage and impaired metabolic signaling, stemming from disrupted brain signaling. Conversely, dieting and physical activity facilitate body weight rebalancing and trigger adaptive neural responses. These adaptations involve the upregulation of neurogenesis, synaptic plasticity and optimized brain function and energy homeostasis, balanced hormone signaling, normal metabolism, and reduced inflammation. The transition of the brain from a maladaptive to an adaptive state is partially guided by epigenetic mechanisms. While epigenetic mechanisms underlying obesity-related brain changes have been described, their role in mediating the reversal of maladaptation/obesity through lifestyle interventions remains less explored. This review focuses on elucidating epigenetic mechanisms involved in hypothalamic adaptations induced by lifestyle interventions. Given that lifestyle interventions are widely prescribed and accessible approaches for weight loss and maintenance, it is our challenge to uncover epigenetic mechanisms moderating these hypothalamic-functional beneficial changes., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Epigenetic regulation of the genome is required for cell-type differentiation during organismal development and is especially important to generate the panoply of specialized cell types that comprise the brain. Here, we review how progressive changes in the chromatin landscape, both in neural progenitors and in postmitotic neurons, orchestrate the timing of gene expression programs that underlie first neurogenesis and then functional neuronal maturation. We discuss how disease-associated mutations in chromatin regulators can change brain composition by impairing the timing of neurogenesis. Further, we highlight studies that are beginning to show how chromatin modifications are integrated at the level of chromatin architecture to coordinate changing transcriptional programs across developmental including in postmitotic neurons., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The oxytocin system plays a role in social stress adaptation, and this role is likely to be particularly important in adolescence. One method of regulating the oxytocin system is through DNA methylation in the promoter of the oxytocin receptor gene (OXTRm), which reduces the gene's expression. This multi-method, longitudinal study, using a diverse community sample of 184 adolescents followed from age 13-28, examined the links between OXTRm and exposure to over-controlling parenting in adolescence and conflict with romantic partners and internalizing symptoms in adulthood. Female, but not male, adolescents who were exposed to psychologically controlling parenting at age 13 had lower levels of OXTRm at site -924 at age 28. Reduced OXTRm at site -924 was associated with greater romantic partner-reported relationship conflict at age 27, and reduced OXTRm at site -934 was marginally associated with greater participant-reported conflict for males. Reduced OXTRm at site -924 was also associated with fewer internalizing symptoms at ages 24-25. These results in adulthood are consistent with an upregulated oxytocin system reducing the salience of negative socioemotional stimuli. Overall, findings are consistent with oxytocin playing a role in the stress response system, and more specifically, by helping us to adapt to social environments like parenting and romantic relationships, reducing the salience of negativity, and reducing risk for common emotional problems., 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 Ltd. All rights reserved.)

Histone lysine lactylation (Kla) has emerged as a distinct epigenetic modification that differs markedly from established acylation modifications through the unique addition of a lactyl group to a lysine residue. Such modifications not only alter nucleosome structure but also significantly impact chromatin dynamics and gene expression, thus playing a crucial role in cellular metabolism, inflammatory responses, and embryonic development. The association of histone Kla with various metabolic processes, particularly glycolysis and glutamine metabolism, underscores its pivotal role in metabolic reprogramming, including in cancerous tissues, where it contributes to tumorigenesis, immune evasion, and angiogenesis. In addition, histone Kla is involved in the pathogenesis of various diseases, particularly several cancers and neurodegenerative diseases. The identification of histone Kla opens new avenues for therapeutic interventions targeting specific Kla sites. In this review, we summarize the differences between histone Kla modifications and other acylation modifications, discuss the mechanisms and roles of histone Kla in disease, and conclude by describing existing drugs and potential targets. This study provides new insights into the mechanisms linking histone Kla to diseases and into the discovery of new drugs and targets., 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 Inc. All rights reserved.)

Genome replication requires duplication of the complete set of DNA sequences together with nucleosomes and epigenetic signatures. Notwithstanding profound knowledge on mechanistic details of DNA replication, major problems of genome replication have remained unresolved. In this perspective article, we consider the accessibility of replication machines to all DNA sequences in due course, the maintenance of functionally important positional and structural features of chromatid domains during replication, and the rapid transition of CTs into prophase chromosomes with two chromatids. We illustrate this problem with EdU pulse-labeling (10 min) and chase experiments (80 min) performed with mouse myeloblast cells. Following light optical serial sectioning of nuclei with 3D structured illumination microscopy (SIM), seven DNA intensity classes were distinguished as proxies for increasing DNA compaction. In nuclei of cells fixed immediately after the pulse-label, we observed a relative under-representation of EdU-labeled DNA in low DNA density classes, representing the active nuclear compartment (ANC), and an over-representation in high density classes representing the inactive nuclear compartment (INC). Cells fixed after the chase revealed an even more pronounced shift to high DNA intensity classes. This finding contrasts with previous studies of the transcriptional topography demonstrating an under-representation of epigenetic signatures for active chromatin and RNAPII in high DNA intensity classes and their over-representation in low density classes. We discuss these findings in the light of current models viewing CDs either as structural chromatin frameworks or as phase-separated droplets, as well as methodological limitations that currently prevent an integration of this contrasting evidence for the spatial nuclear topography of replication and transcription into a common framework of the dynamic nuclear architecture.

Addiction is a leading cause of disease burden worldwide and remains a challenge in current neuroscience research. Drug-induced lasting changes in gene expression are mediated by transcriptional and epigenetic regulation in the brain and are thought to underlie behavioral adaptations. Emerging evidence implicates astrocytes in regulating drug-seeking behaviors and demonstrates robust transcriptional response to several substances of abuse. This review focuses on the astrocytic transcriptional and epigenetic mechanisms of drug action., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Rheumatoid arthritis (RA) is characterized by synovial edema, inflammation, bone and cartilage loss, and joint degradation. Patients experience swelling, stiffness, pain, limited joint movement, and decreased mobility as the condition worsens. RA treatment regimens often come with various side effects, including an increased risk of developing cancer and organ failure, potentially leading to mortality. However, researchers have proposed mechanistic hypotheses to explain the underlying causes of synovitis and joint damage in RA patients. This review article focuses on the role of synoviocytes and synoviocytes resembling fibroblasts in the RA synovium. Additionally, it explores the involvement of epigenetic regulatory systems, such as microRNA pathways, silent information regulator 1 (SIRT1), Peroxisome proliferatoractivated receptor-gamma coactivator (PGC1-α), and protein phosphatase 1A (PPM1A)/high mobility group box 1 (HMGB1) regulators. These mechanisms are believed to modulate the function of receptors, cytokines, and growth factors associated with RA. The review article includes data from preclinical and clinical trials that provide insights into potential treatment options for RA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Interpretation of the histone posttranslational modifications (PTMs) by effector proteins, or readers, is an important epigenetic mechanism to regulate gene function. YEATS domains have been recently identified as novel readers of histone lysine acetylation and a variety of nonacetyl acylation marks. Accumulating evidence has revealed the association of dysregulated interactions between YEATS domains and histone PTMs with human diseases, suggesting the therapeutic potential of YEATS domain inhibition. Here, we discuss the molecular mechanisms adopted by YEATS domains in recognizing their preferred histone marks and the biological significance of such recognitions in normal cell physiology and pathogenesis of human diseases. Recent progress in the development of YEATS domain inhibitors is also discussed.

Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at "stemness" genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating "stemness" genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases.

Background: Collagen type XII alpha 1 chain (COL12A1) is associated with human cancer progression. Nevertheless, the expression pattern and the function of COL12A1 in intrahepatic cholangiocarcinoma (iCCA) remain unknown. The present study was performed to assess the role of COL12A1 in iCCA., Results: A total of 1669 genes, differentially expressed between iCCA and nontumor liver tissue samples, were identified as potential tumor-specific biomarkers for iCCA patients. Of these, COL12A1 was significantly upregulated in clinical iCCA tissue samples and correlated with epithelial-mesenchymal transition gene set enrichment score and advanced tumor stage in clinical iCCA. COL12A1-high expression was associated with the poor prognoses of iCCA patients (n = 421) from four independent cohorts. Promoter hypermethylation-induced downregulation of miR-424-5p resulted in COL12A1 upregulation in clinical iCCA. Experimental knockout of COL12A1 inhibited the proliferation, invasiveness and growth of iCCA cells. MiR-424-5p had a therapeutic potential in iCCA via directly targeting COL12A1., Conclusions: Promoter hypermethylation-induced miR-424-5p downregulation contributes to COL12A1 upregulation in iCCA. COL12A1 is a promising druggable target for epigenetic therapy of iCCA., (© 2023. The Author(s).)

Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrP C ) known as PrP Sc . DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes ( DNMT1 , DNMT3A , DNMT3B , HDAC1 , HDAC2 , TET1 , and TET2 ) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b , Hdac1 , and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases.

Aims: To explore the methylation status, function, and underlying mechanism of the imprinted gene Neuronatin (NNAT) in hepatocellular carcinoma (HCC) progression., Main Methods: Immunohistochemistry (IHC) was performed to evaluate the expression of NNAT in HCC samples. Bisulfite genomic sequencing PCR (BSP) was applied to examine the methylation status of the NNAT promoter. In addition, colony formation, 5-Ethynyl-20-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of NNAT in HCC cell proliferation. Furthermore, RNA-seq and phospho-specific protein microarray assays were conducted to illustrate the underlying mechanism by which NNAT regulates HCC progression., Key Findings: NNAT was obviously downregulated in HCC tissues, and its expression level was closely associated with tumor growth and patient prognosis. The downregulation of NNAT in HCC was induced by hypermethylation of CpG islands in the promoter region, and hypermethylation was correlated with overall survival of HCC. Moreover, the enforced expression of NNAT significantly inhibited HCC cell proliferation in vitro and in vivo. Transcriptome analysis showed that the alteration of NNAT expression was mainly related to dysregulation of the PI3K-Akt signaling pathway. Finally, phospho-specific antibody microarray detection further revealed that overexpressed NNAT can increase the phosphorylation levels of LKB1, Met, and elF4E and decrease the phosphorylation levels of PTEN, which are all involved in the PI3K-Akt signaling pathway., Significance: Our research provides new insights into the epigenetic regulation of imprinted genes in tumorigenesis and implies that the imprinted gene NNAT may act as a prognostic biomarker and tumor suppressor in HCC., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations., Significance: Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer., (©2022 American Association for Cancer Research.)

The conserved plasmodial surface anion channel (PSAC) mediates nutrient uptake by bloodstream malaria parasites and is an antimalarial target. This pathogen-associated channel is linked to the clag multigene family, which is variably expanded in Plasmodium spp. Member genes are under complex epigenetic regulation, with the clag3 genes of the human P. falciparum pathogen exhibiting monoallelic transcription and mutually exclusive surface exposure on infected erythrocytes. While other multigene families use monoallelic expression to evade host immunity, the reasons of epigenetic control of clag genes are unclear. I consider existing models and their implications for nutrient acquisition and immune evasion. Understanding the reasons for epigenetic regulation of PSAC-mediated nutrient uptake will help clarify host-pathogen interactions and guide development of therapies resistant to allele switching., Competing Interests: Declaration of interests The author declares no competing interests., (Published by Elsevier Ltd.)

Importance: Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality., Objective: We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women., Design, Setting, and Participants: This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021., Exposures: EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim., Main Outcomes and Measures: Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years., Results: Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72; P < .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98; P = .03) compared with women who did not survive to age 90 years., Conclusions and Relevance: These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.

The pandemic of COVID-19 has caused >5 million deaths in the world. One of the leading causes of the severe form of COVID-19 is the production of massive amounts of proinflammatory cytokines. Epigenetic mechanisms, such as histone/DNA methylation, miRNA, and long noncoding RNA, are known to play important roles in the regulation of inflammation. In this study, we investigated if hospitalized COVID-19 patients exhibit alterations in epigenetic pathways in their PBMCs. We also compared gene expression profiles between healthy controls and COVID-19 patients. Despite individual variations, the expressions of many inflammation-related genes, such as arginase 1 and IL-1 receptor 2, were significantly upregulated in COVID-19 patients. We also found the expressions of coagulation-related genes Von Willebrand factor and protein S were altered in COVID-19 patients. The expression patterns of some genes, such as IL-1 receptor 2, correlated with their histone methylation marks. Pathway analysis indicated that most of those dysregulated genes were in the TGF-β, IL-1b, IL-6, and IL-17 pathways. A targeting pathway revealed that the majority of those altered genes were targets of dexamethasone, which is an approved drug for COVID-19 treatment. We also found that the expression of bone marrow kinase on chromosome X, a member of TEC family kinases, was increased in the PBMCs of COVID-19 patients. Interestingly, some inhibitors of TEC family kinases have been used to treat COVID-19. Overall, this study provides important information toward identifying potential biomarkers and therapeutic targets for COVID-19 disease., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Alterations in the nutritional environment in early life can significantly increase the risk for obesity and a range of development of metabolic disorders in offspring in later life, effects that can be passed onto future generations. This process, termed development programming, provides the framework of the developmental origins of health and disease (DOHaD) paradigm. Early life nutritional compromise including undernutrition, overnutrition or specific macro/micronutrient deficiencies, results in a range of adverse health outcomes in offspring that can be further exacerbated by a poor postnatal nutritional environment. Although the mechanisms underlying programming remain poorly defined, a common feature across the phenotypes displayed in preclinical models is that of altered wiring of neuroendocrine circuits that regulate satiety and energy balance. As such, altered maternal nutritional exposures during critical early periods of developmental plasticity can result in aberrant hardwiring of these circuits with lasting adverse consequences for the offspring. There is also increasing evidence around the role of an altered epigenome and the gut-brain axis in mediating some of the central programming effects observed. Further, although such programming was once considered to result in a permanent change in developmental trajectory, there is evidence, at least from preclinical models, that programming can be reversed via targeted nutritional manipulations during early development. Further work is required at a mechanistic level to allow for identification for early markers of later disease risk, delineation of sex-specific effects and pathways to implementation of strategies aimed at breaking the transgenerational transmission of disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Testicular aromatase catalyzes the synthesis of estradiol, which contributes to regulation of porcine Sertoli cell proliferation and postpubertal maintenance of Sertoli cell numbers. Although aromatase enzymatic activity decreases with age and is persistently reprogrammed by prepubertal treatment with the aromatase inhibitor letrozole, the molecular bases for regulation have not been identified. DNA methylation was examined as a potential regulatory mechanism using DNA from Leydig cells isolated from 16-, 40-, and 68-week-old boars and from 68- week-old littermates treated with the aromatase inhibitor, letrozole. Methylation levels of individual CpG dinucleotides located in the distal untranslated exon 1 of the relevant aromatase encoding gene, CYP19A3, were quite high in Leydig cell DNA, and increased further with maturity of boar (P < 0.05), while aromatase activity and transcript abundance decreased more than two-fold. However, reduced aromatase activity following letrozole treatment was not accompanied by altered DNA methylation. Testicular expression of miR378 was altered by prepubertal treatment with letrozole. The data provide evidence for two different epigenetic mechanisms that regulate aromatase expression and enzymatic activity in the boar testis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The mechanisms by which sex is determined, and how a sexual phenotype is stably maintained during adulthood, have been the focus of vigorous scientific inquiry. Resources common to the biomedical field (automated staining and imaging platforms) were leveraged to provide the first immunofluorescent data for a reptile species with temperature induced sex reversal. Two four-plex immunofluorescent panels were explored across three sex classes (sex reversed ZZf females, normal ZWf females, and normal ZZm males). One panel was stained for chromatin remodeling genes JARID2 and KDM6B, and methylation marks H3K27me3, and H3K4me3 (Jumonji Panel). The other CaRe panel stained for environmental response genes CIRBP and RelA, and H3K27me3 and H3K4me3. Our study characterized tissue specific expression and cellular localization patterns of these proteins and histone marks, providing new insights to the molecular characteristics of adult gonads in a dragon lizard Pogona vitticeps. The confirmation that mammalian antibodies cross react in P. vitticeps paves the way for experiments that can take advantage of this new immunohistochemical resource to gain a new understanding of the role of these proteins during embryonic development, and most importantly for P. vitticeps, the molecular underpinnings of sex reversal., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The epigenetic clock parameter DNAm age acceleration is a promising biomarker of aging. We have recently described an epigenetic clock based on only seven cytosine-phosphate-guanine sites, which is highly associated with chronological age. The aim of this study was to examine this epigenetic clock with respect to its relationship with cardiovascular health (CVH) in older adults. We used data from the Berlin Aging Study II (BASE-II; 1,671 participants; 68.8 ± 3.7 years old). CVH was operationalized using two different CVH scores, the Framingham Risk Score (FRS), and the Life's simple 7 (LS7). To adjust for potential confounding, e.g. by sex, we performed regression analyses. The LS7 score was higher, i.e. more favorable, in woman than in men (8.8 ± 2 vs. 8.2 ± 2, p < 0.001). DNAm age acceleration was associated with the FRS (β = 0.122, p = 0.028) and with the LS7 (β = -0.804, p = 0.032). In more detail, physical activity (β = -0.461, p = 0.05), HDL-cholesterol (β = 0.343, p = 0.03) and total cholesterol (β = -0.364, p = 0.002) were associated with epigenetic age acceleration. We present evidence suggesting that better CVH is associated with decelerated biological aging measured by the epigenetic clock., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite several decades of research and prevention efforts, fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of neurodevelopmental disabilities worldwide. Animal and human studies have implicated fetal alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD. Several studies have demonstrated fetal alcohol-related alterations in methylation and expression of imprinted genes in placental, brain, and embryonic tissue. Imprinted genes are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The chief functions of imprinted genes are in placental development, somatic growth, and neurobehavior-three domains characteristically affected in FASD. In this review, we summarize the growing body of literature characterizing prenatal alcohol-related alterations in imprinted gene methylation and/or expression and discuss potential mechanistic roles for these alterations in the teratogenic effects of prenatal alcohol exposure. Future research is needed to examine potential physiologic mechanisms by which alterations in imprinted genes disrupt development in FASD, which may, in turn, elucidate novel targets for intervention. Furthermore, mechanistic alterations in imprinted gene expression and/or methylation in FASD may inform screening assays that identify individuals with FASD neurobehavioral deficits who may benefit from early interventions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Muscle fibers are syncytial postmitotic cells that can acquire exogenous nuclei from resident muscle stem cells, called satellite cells. Myonuclei are added to muscle fibers by satellite cells during conditions such as load-induced hypertrophy. It is difficult to dissect the molecular contributions of resident versus satellite cell-derived myonuclei during adaptation due to the complexity of labeling distinct nuclear populations in multinuclear cells without label transference between nuclei. To sidestep this barrier, we used a genetic mouse model where myonuclear DNA can be specifically and stably labeled via nonconstitutive H2B-GFP at any point in the lifespan. Resident myonuclei (Mn) were GFP-tagged in vivo before 8 wk of progressive weighted wheel running (PoWeR) in adult mice (>4-mo-old). Resident + satellite cell-derived myonuclei (Mn+SC Mn) were labeled at the end of PoWeR in a separate cohort. Following myonuclear isolation, promoter DNA methylation profiles acquired with low-input reduced representation bisulfite sequencing (RRBS) were compared to deduce epigenetic contributions of satellite cell-derived myonuclei during adaptation. Resident myonuclear DNA has hypomethylated promoters in genes related to protein turnover, whereas the addition of satellite cell-derived myonuclei shifts myonuclear methylation profiles to favor transcription factor regulation and cell-cell signaling. By comparing myonucleus-specific methylation profiling to previously published single-nucleus transcriptional analysis in the absence (Mn) versus the presence of satellite cells (Mn+SC Mn) with PoWeR, we provide evidence that satellite cell-derived myonuclei may preferentially supply specific ribosomal proteins to growing myofibers and retain an epigenetic "memory" of prior stem cell identity. These data offer insights on distinct epigenetic myonuclear characteristics and contributions during adult muscle growth.

Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka ( Oryzias melastigma ), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP-BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.

Background: N 6 -methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution., Methods: We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N =48; subcutaneous adipose tissue (SAT) N =56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT ( N =46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population ( N =1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits., Results: In adipose tissue we observed that several m6A regulators ( WTAP , VIRMA , YTHDC1 and ALKBH5 ) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3 , WTAP , VIRMA , FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression., Conclusions: Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences., 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 © 2021 Rønningen, Dahl, Valderhaug, Cayir, Keller, Tönjes, Blüher and Böttcher.)

Mast cells are immune cells that store large amounts of mast cell-restricted proteases in their secretory granules, including tryptase, chymase and carboxypeptidase A3. In mouse mast cells, it has been shown that tryptase, in addition to its canonical location in secretory granules, can be found in the nuclear compartment where it can impact on core histones. Here we asked whether tryptase can execute core histone processing in human mast cell leukemia cells, and whether tryptase thereby can affect the epigenetic modification of core histones. Our findings reveal that triggering of cell death in HMC-1 mast cell leukemia cells is associated with extensive cleavage of core histone 3 (H3) and more restricted cleavage of H2B. Tryptase inhibition caused a complete blockade of such processing. Our data also show that HMC-1 cell death was associated with a major reduction of several epigenetic histone marks, including H3 lysine-4-mono-methylation (H3K4me1), H3K9me2, H3 serine-10-phosphorylation (H3S10p) and H2B lysine-16-acetylation (H2BK16ac), and that tryptase inhibition reverses the effect of cell death on these epigenetic marks. Further, we show that tryptase is present in the nucleus of both viable and dying mast cell leukemia cells. In line with a role for tryptase in regulating nuclear events, tryptase inhibition caused increased proliferation of the mast cell leukemia cells. Altogether, the present study emphasizes a novel principle for how epigenetic modification of core histones is regulated, and provides novel insight into the biological function of human mast cell tryptase., 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 © 2021 Alanazi, Rabelo Melo and Pejler.)

Transposable elements (TEs) contribute to genomic innovations, as well as genome instability, across a wide variety of species. Popular designations such as 'selfish DNA' and 'junk DNA,' common in the 1980s, may be either inaccurate or misleading, while a more enlightened view of the TE-host relationship covers a range from parasitism to mutualism. Both plant and animal hosts have evolved epigenetic mechanisms to reduce the impact of TEs, both by directly silencing them and by reducing their ability to transpose in the genome. However, TEs have also been co-opted by both plant and animal genomes to perform a variety of physiological functions, ranging from TE-derived proteins acting directly in normal biological functions to innovations in transcription factor activity and also influencing gene expression. Their presence, in fact, can affect a range of features at genome, phenotype, and population levels. The impact TEs have had on evolution is multifaceted, and many aspects still remain unexplored. In this review, the epigenetic control of TEs is contextualized according to the evolution of complex living systems., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6-13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, "Metabolic Decisions in Development and Disease." The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism., (© 2021 New York Academy of Sciences.)

Background: The thymic microenvironment is mainly comprised of thymic epithelial cells, the cytokines, exosomes, surface molecules, and hormones from the cells, and plays a vital role in the development, differentiation, maturation and homeostasis of T lymphocytes. However, the thymus begins to degenerate as early as the second year of life and continues through aging in human beings, leading to a decreased output of naïve T cells, the limited TCR diversity and an expansion of monoclonal memory T cells in the periphery organs. These alternations will reduce the adaptive immune response to tumors and emerging infectious diseases, such as COVID-19, also it is easier to suffer from autoimmune diseases in older people. In the context of global aging, it is important to investigate and clarify the causes and mechanisms of thymus involution., Main Body: Epigenetics include histone modification, DNA methylation, non-coding RNA effects, and chromatin remodeling. In this review, we discuss how senescent thymic epithelial cells determine and control age-related thymic atrophy, how this process is altered by epigenetic modification. How the thymus adipose influences the dysfunctions of the thymic epithelial cells, and the prospects of targeting thymic epithelial cells for the treatment of thymus atrophy., Conclusion: Epigenetic modifications are emerging as key regulators in governing the development and senescence of thymic epithelial cells. It is beneficial to re-establish effective thymopoiesis, identify the potential therapeutic strategy and rejuvenate the immune function in the elderly., (© 2021. The Author(s).)

Background: GGC repeat expansions in NOTCH2NLC are associated with neuronal intranuclear inclusion disease. Very recently, asymptomatic carriers with NOTCH2NLC repeat expansions were reported. In these asymptomatic individuals, the CpG island in NOTCH2NLC is hypermethylated, suggesting that two factors repeat length and DNA methylation status should be considered to evaluate pathogenicity. Long-read sequencing can be used to simultaneously profile genomic and epigenomic alterations. We analyzed four sporadic cases with NOTCH2NLC repeat expansion and their phenotypically normal parents. The native genomic DNA that retains base modification was sequenced on a per-trio basis using both PacBio and Oxford Nanopore long-read sequencing technologies. A custom workflow was developed to evaluate DNA modifications. With these two technologies combined, long-range DNA methylation information was integrated with complete repeat DNA sequences to investigate the genetic origins of expanded GGC repeats in these sporadic cases., Results: In all four families, asymptomatic fathers had longer expansions (median: 522, 390, 528 and 650 repeats) compared with their affected offspring (median: 93, 117, 162 and 140 repeats, respectively). These expansions are much longer than the disease-causing range previously reported (in general, 41-300 repeats). Repeat lengths were extremely variable in the father, suggesting somatic mosaicism. Instability is more frequent in alleles with uninterrupted pure GGCs. Single molecule epigenetic analysis revealed complex DNA methylation patterns and epigenetic heterogeneity. We identified an aberrant gain-of-methylation region (2.2 kb in size beyond the CpG island and GGC repeats) in asymptomatic fathers. This methylated region was unmethylated in the normal allele with bilateral transitional zones with both methylated and unmethylated CpG dinucleotides, which may be protected from methylation to ensure NOTCH2NLC expression., Conclusions: We clearly demonstrate that the four sporadic NOTCH2NLC-related cases are derived from the paternal GGC repeat contraction associated with demethylation. The entire genetic and epigenetic landscape of the NOTCH2NLC region was uncovered using the custom workflow of long-read sequence data, demonstrating the utility of this method for revealing epigenetic/mutational changes in repetitive elements, which are difficult to characterize by conventional short-read/bisulfite sequencing methods. Our approach should be useful for biomedical research, aiding the discovery of DNA methylation abnormalities through the entire genome., (© 2021. The Author(s).)

In addition to DNA methylation, reversible epigenetic modification occurring in RNA has been discovered recently. The most abundant type of RNA methylation is N6-methyladenosine (m6A) modification, which is dynamically regulated by methylases ("writers"), demethylases ("erasers") and m6A-binding proteins ("readers"). As an essential posttranscriptional regulator, m6A can control mRNA splicing, processing, stability, export and translation. Recent studies have revealed that m6A modification has the strongest tissue specificity for brain tissue and plays crucial roles in central nervous system (CNS) injures by affecting its downstream target genes or non-coding RNAs. This review focuses on the expression and function of m6A regulatory proteins in CNS trauma in vitro and in vivo. We also highlight the latest insights into the molecular mechanisms of pathological damage in the CNS. Understanding m6A dynamics, functions, and machinery will yield an opportunity for designing and developing novel therapeutic agents for CNS injuries., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neuroinflammation is a key factor of the pathology of various neurological diseases (brain injury, depression, neurodegenerative diseases). It is a complex and orderly process that relies on various types of glial cells and peripheral immune cells. Inhibition of neuroinflammation can reduce the severity of neurological diseases. The initiation, progression, and termination of inflammation require gene activation, epigenetic modification, transcriptional translation, and post-translational regulation, all of which are tightly regulated by different enzymes. Epigenetics refers to the regulation of epigenetic gene expression by epigenetic changes (DNA methylation, histone modification, and non-coding RNAs such as miRNA) that are not dependent on changes in gene sequence and are heritable. Histone deacetylases (HDACs) are a group of important enzymes that regulate epigenetics. They can remove the acetyl group on the lysine ϵ-amino group of the target protein, thereby affecting gene transcription or altering protein activity. HDACs are involved in the regulation of immunity and inflammation. HDAC inhibitor (HDACi) has also become a new hotspot in the research of anti-inflammatory drugs. Therefore, the aim of the current review is to discuss and summarize the role and mechanism of different HDACs in neuroinflammation and the corresponding role of HDACi in neurological diseases, and to providing new ideas for future research on neuroinflammation-related diseases and drug development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Environmental exposure to arsenic, a well-established carcinogen linked to a number of human cancers, is a public health concern in many areas of the world. Despite extensive studies on the molecular mechanisms of arsenic-induced carcinogenesis, how initial cellular responses, such as activation of stress kinases and the generation of reactive oxygen species, converge to affect the transcriptional and/or epigenetic reprogramming required for the malignant transformation of normal cells or normal stem cells remains to be elucidated. In this review, we discuss some recent discoveries showing how the transcription factor NRF2 and an epigenetic regulator, MDIG, contribute to the arsenic-induced generation of cancer stem-like cells (CSCs) as determined by applying CRISPR-Cas9 gene editing and chromosome immunoprecipitation followed by DNA sequencing (ChIP-seq)., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that 'non-coding' does not mean 'non-essential' and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA., (© 2021. Springer Nature Limited.)

Islet function is critical for normal glucose homeostasis. Unlike adult β cells, fetal and neonatal islets are more proliferative and have decreased insulin secretion in response to stimuli. However, the underlying mechanisms governing functional maturity of islets have not been completely elucidated. Pancreatic islets comprise different cell types. The microenvironment of islets and interactions between these cell types are critical for β-cell development and maturation. Thus, the study of intact islets is optimal to identify novel molecular mechanisms controlling islet functional development. Transcriptomes and genome-wide histone landscapes of H3K4me3, H3K27me3, and H3K27Ac from intact islets isolated from 2- and 10-week-old Sprague-Dawley rats were integrated to elucidate genes and pathways modulating islet development, as well as the contribution of epigenetic regulation. A total of 4489 differentially expressed genes were identified; 2289 and 2200 of them were up- and down-regulated in 10-week islets, respectively. Ingenuity Pathway Analysis revealed critical pathways regulating functional maturation of islets, including nutrient sensing, neuronal function, immune function, cell replication, and extracellular matrix. Furthermore, we identified significant changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac marks, which correlated with expression changes of genes critical for islet function. These histone marks were enriched at critical transcription factor-binding motifs, such as Hoxa9, C/EBP-β, Gata1, Foxo1, E2f1, E2f3, and Mafb. In addition, our chromatin immunoprecipitation sequencing data revealed multiple potential bivalent genes whose poised states changed with maturation. Collectively, our current study identified critical novel pathways for mature islet function and suggested a role for histone modifications in regulating islet development and maturation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The central dogma of molecular genetics is defined as encoded genetic information within DNA, transcribed into messenger RNA, which contain the instructions for protein synthesis, thus imparting cellular functionality and ultimately life. This molecular genetic theory has given birth to the field of neuroepigenetics, and it is now well established that epigenetic regulation of gene transcription is critical to the learning and memory process. In this review, we address a potential role for a relatively new player in the field of epigenetic crosstalk - long non-coding RNAs (lncRNAs). First, we briefly summarize epigenetic mechanisms in memory formation and examine what little is known about the emerging role of lncRNAs during this process. We then focus discussions on how lncRNAs interact with epigenetic mechanisms to control transcriptional programs under various conditions in the brain, and how this may be applied to regulation of gene expression necessary for memory formation. Next, we explore how epigenetic crosstalk in turn serves to regulate expression of various individual lncRNAs themselves. To highlight the importance of further exploring the role of lncRNA in epigenetic regulation of gene expression, we consider the significant relationship between lncRNA dysregulation and declining memory reserve with aging, Alzheimer's disease, and epilepsy, as well as the promise of novel therapeutic interventions. Finally, we conclude with a discussion of the critical questions that remain to be answered regarding a role for lncRNA in memory., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability., Methods: Female rats (n = 8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw of the rats respectively. All rats were returned to SH for 3 weeks before colonic and somatic sensitivity were reassessed on day 28. The rats were then immediately euthanized and the spinal cord was collected to assess changes in neuronal activation (assessed via ERK phosphorylation) in response to noxious CRD. A separate cohort of animals (n = 8/group) that did not undergo behavioral assessments was euthanized the day after the final WAS exposure and the central nucleus of the amygdala (CeA) was collected to investigate WAS and EE induced epigenetic changes at the glucocorticoid receptor (GR) and corticotrophin releasing hormone (CRH) promoter. The colon from these rats was also collected to assess colonic permeability via changes in transepithelial electrical resistance (TEER) in vitro., Results: Exposure to stress persistently increased VMR to CRD (P < 0.01) and decreased the hind paw withdrawal threshold (P < 0.001) in female rats. WAS also decreased TEER in the colon tissue of female rats (p = 0.05). In the CeA, WAS induced a decrease in histone acetylation at the GR promoter but increased histone acetylation at the CRH promoter and reduced GR-CRH interactions in the CeA. Analysis of the spinal cord showed that WAS increased CRD-evoked ERK phosphorylation in the dorsal horn. Exposure to EE prevented WAS-induced changes in the CeA, dorsal horn and colon respectively to prevent visceral and somatic hypersensitivity., Conclusion: Our data reveals that behavioral therapies can produce long lasting molecular and epigenetic changes that can prevent stress-induced pathologies even after completion of the therapy. These results highlight the potential mechanisms by which behavioral therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A critical shortcoming of the central nervous system is its limited ability to repair injured nerve connections. Trying to overcome this limitation is not only relevant to understand basic neurobiological principles but also holds great promise to advance therapeutic strategies related, in particular, to spinal cord injury (SCI). With barely any SCI patients re-gaining complete neurological function, there is a high need to understand how we could target and improve spinal plasticity to re-establish neuronal connections into a functional network. The development of chemogenetic tools has proven to be of great value to understand functional circuit wiring before and after injury and to correlate novel circuit formation with behavioral outcomes. This review covers commonly used chemogenetic approaches based on metabotropic receptors and their use to improve our understanding of circuit wiring following spinal cord injury., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Regular physical exercise improves health by reducing the risk of a plethora of chronic disorders. We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle and that this remodeling contributes to the beneficial effects of exercise on human health., Methods and Results: By studying changes in histone modifications, we mapped the genome-wide positions and activities of enhancers in skeletal muscle biopsies collected from young sedentary men before and after 6 weeks of endurance exercise. We identified extensive remodeling of enhancer activities after exercise training, with a large subset of the remodeled enhancers located in the proximity of genes transcriptionally regulated after exercise. By overlapping the position of enhancers with genetic variants, we identified an enrichment of disease-associated genetic variants within the exercise-remodeled enhancers., Conclusion: Our data provide evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)