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Nucleosome dynamics plays important roles in many biological processes, such as DNA replication and gene expression. NucMap (https://ngdc.cncb.ac.cn/nucmap) is the first database of genome-wide nucleosome positioning maps across species. Here, we present an updated version, NucMap 2.0, by incorporating more species and MNase-seq samples. In addition, we integrate other related omics data for each MNase-seq sample to provide a comprehensive view of nucleosome positioning, such as gene expression, transcription factor binding sites, histone modifications and DNA methylation. In particular, NucMap 2.0 integrates and pre-analyzes RNA-seq data and ChIP-seq data of human-related samples, which facilitates the interpretation of nucleosome positioning in humans. All processed data are integrated into an in-built genome browser, and users can make comprehensive side-by-side analyses. In addition, more online analytical functions are developed, which allows researchers to identify differential nucleosome regions and explore potential gene regulatory regions. All resources are open access with a user-friendly web interface., 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.)

Understanding the regulatory mechanisms of gene expression is a crucial objective in genomics. Although the DNA sequence near the transcription start site (TSS) offers valuable insights, recent methods suggest that analyzing only the surrounding DNA may not suffice to accurately predict gene expression levels. We developed GENet (Gene Expression Network from Histone and Transcription Factor Integration), a novel approach that integrates essential regulatory signals from transcription factors and histone modifications into a graph-based model. GENet extends beyond simple DNA sequence analysis by incorporating additional layers of genetic control, which are vital for determining gene expression. Our method markedly enhances the prediction of mRNA levels compared to previous models that depend solely on DNA sequence data. The results underscore the significance of including comprehensive regulatory information in gene expression studies. GENet emerges as a promising tool for researchers, with potential applications extending from fundamental biological research to the development of medical therapies.

In recent years, the exploration of genome three-dimensional (3D) conformation has yielded profound insights into the regulation of gene expression and cellular functions in both animals and plants. While animals exhibit a characteristic genome topology defined by topologically associating domains (TADs), plants display similar features with a more diverse conformation across species. Employing advanced high-throughput sequencing and microscopy techniques, we investigated the landscape of 26 histone modifications and RNA polymerase II distribution in tomato ( Solanum lycopersicum ). Our study unveiled a rich and nuanced epigenetic landscape, shedding light on distinct chromatin states associated with heterochromatin formation and gene silencing. Moreover, we elucidated the intricate interplay between these chromatin states and the overall topology of the genome. Employing a genetic approach, we delved into the role of the histone modification H3K9ac in genome topology. Notably, our investigation revealed that the ectopic deposition of this chromatin mark triggered a reorganization of the 3D chromatin structure, defining different TAD-like borders. Our work emphasizes the critical role of H3K9ac in shaping the topology of the tomato genome, providing valuable insights into the epigenetic landscape of this agriculturally significant crop species., Competing Interests: Competing interests statement:The authors declare no competing interest.

Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.

Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone a resurgence in scientific interest since the discovery of the Warburg effect in tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair the function of immune cells within tumor microenvironments. Nevertheless, the precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, lactic acid has been found to induce a posttranslational modification, lactylation, that may offer insight into lactic acid's non-metabolic functions. Notably, the posttranslational modification of proteins by lactylation has emerged as a crucial mechanism by which lactate regulates cellular processes. This article provides an overview of the discovery of lactate acidification, outlines the potential "writers" and "erasers" responsible for protein lactylation, presents an overview of protein lactylation patterns across different organisms, and discusses the diverse physiological roles of lactylation. Besides, the article highlights the latest research progress concerning the regulatory functions of protein lactylation in pathological processes and underscores its scientific significance for future investigations., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss, imposing a significant burden on affected individuals and their families. Despite the recent promising progress in therapeutic approaches, more needs to be done to understand the intricate molecular mechanisms underlying the development and progression of AD. Growing evidence points to epigenetic changes as playing a pivotal role in the pathogenesis of the disease. The dynamic interplay between genetic and environmental factors influences the epigenetic landscape in AD, altering gene expression patterns associated with key pathological events associated with disease pathogenesis. To this end, epigenetic alterations not only impact the expression of genes implicated in AD pathogenesis but also contribute to the dysregulation of crucial cellular processes, including synaptic plasticity, neuroinflammation, and oxidative stress. Understanding the complex epigenetic mechanisms in AD provides new avenues for therapeutic interventions. This review comprehensively examines the role of DNA methylation and histone modifications in the context of AD. It aims to contribute to a deeper understanding of AD pathogenesis and facilitate the development of targeted therapeutic strategies.

Ovarian cancer (OC) is a deadly disease with limited treatment options and poor overall survival rates. This study aimed to investigate the role of histone modification-related genes in predicting the prognosis of OC patients. Transcriptome data from multiple cohorts, including bulk RNA-Seq data and single-cell scRNA-Seq data, were collected. Gene set enrichment analysis was used to identify enriched gene sets in the histone modification pathway. Differentially expressed genes (DEGs) between histone modification-high and histone modification-low groups were identified using Lasso regression. A prognostic model was constructed using five selected prognostic genes from the DEGs in the TCGA-OV cohort. The study found enrichment of gene sets in the histone modification pathway and identified five prognostic genes associated with OC prognosis. The constructed risk score model based on histone modification-related genes was correlated with immune infiltration of T cells and M1 macrophages. Mutations are more prevalent in the high-risk group compared to the low-risk group. Several drugs were screened against the model genes. Through in vitro experiments, we confirmed the expression patterns of the model genes. LBX2 facilitates the proliferation of OC. Histone modification-related genes have the potential to serve as biomarkers for predicting OC prognosis. Targeting these genes may lead to the development of more effective therapies for OC. Additionally, LBX2 represents a novel cell proliferation promoter in OC carcinogenesis., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Telomere integrity is required for the maintenance of genome stability and prevention of oncogenic transformation of cells. Recent evidence suggests the presence of epigenetic modifications as an important regulator of mammalian telomeres. Telomeric and subtelomeric regions are rich in epigenetic marks that regulate telomere length majorly through DNA methylation and post-translational histone modifications. Specific histone modifying enzymes play an integral role in establishing telomeric histone codes necessary for the maintenance of structural integrity. Alterations of crucial histone moieties and histone modifiers cause deregulations in the telomeric chromatin leading to carcinogenic manifestations. This review delves into the significance of histone modifications and their influence on telomere dynamics concerning cancer. Additionally, it highlights the existing research gaps that hold the potential to drive the development of therapeutic interventions targeting the telomere epigenome., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Despite extensive research over the last few decades, the etiology of schizophrenia (SZ) remains unclear. SZ is a pathological disorder that is highly debilitating and deeply affects the lifestyle and minds of those affected. Several factors (one or in combination) have been reported as contributors to SZ pathogenesis, including neurodevelopmental, environmental, genetic and epigenetic factors. Deoxyribonucleic acid (DNA) methylation and post-translational modification (PTM) of histone proteins are potentially contributing epigenetic processes involved in transcriptional activity, chromatin folding, cell division and apoptotic processes, and DNA damage and repair. After establishing a summary of epigenetic processes in the context of schizophrenia, this review aims to highlight the current understanding of the role of DNA methylation and histone PTMs in this disorder and their potential roles in schizophrenia pathophysiology and pathogenesis.

In traditional cell line design pipelines, cost- and time-intensive long-term stability studies must be performed due to random integration of the transgene into the genome. By this, integration into epigenetically silenced regions can lead to silencing of the recombinant promoter over time. Site-specific integration into regions with active chromatin structure can overcome this problem and lead to strong and stable gene expression. Here, we describe a detailed protocol to identify integration sites with epigenetically preferable properties by chromatin immunoprecipitation sequencing and use them for stable and strong gene expression by applying CRISPR/Cas9. Furthermore, the examination of the integration sites with focus on Cas9-targeted sequencing with nanopores is described., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The human and mouse genomes are complex from a genomic standpoint. Each cell has the same genomic sequence, yet a wide array of cell types exists due to the presence of a plethora of regulatory elements in the non-coding genome. Recent advances in epigenomic profiling have uncovered non-coding gene proximal promoters and distal enhancers of transcription genome-wide. Extension of promoter-associated H3K4me3 histone mark across the gene body, known as a broad H3K4me3 domain (H3K4me3-BD), is a signature of constitutive expression of cell-type-specific regulation and of tumour suppressor genes in healthy cells. Recently, it has been discovered that the presence of H3K4me3-BDs over oncogenes is a cancer-specific feature associated with their dysregulated gene expression and tumourigenesis. Moreover, it has been shown that the hijacking of clusters of enhancers, known as super-enhancers (SE), by proto-oncogenes results in the presence of H3K4me3-BDs over the gene body. Therefore, H3K4me3-BDs and SE crosstalk in healthy and cancer cells therefore represents an important mechanism to identify future treatments for patients with SE driven cancers., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

Allele specific expression (ASE) is widespread in many species including cows. Therefore, regulatory regions which control gene expression should show cis-regulatory variation which mirrors this differential expression within the animal. ChIP-seq peaks for histone modifications and transcription factors measure activity at functional regions and the height of some peaks have been shown to correlate across tissues with the expression of particular genes, suggesting these peaks are putative regulatory regions. In this study we identified ASE in the bovine genome in multiple tissues and investigated whether ChIP-seq peaks for four histone modifications and the transcription factor CTCF show allele specific binding (ASB) differences in the same tissues. We then investigate whether peak height and gene expression, which correlates across tissues, also correlates within the animal by investigating whether the direction of ASB in putative regulatory regions, mirrors that of the ASE in the genes they are putatively regulating. We found that ASE and ASB were widespread in the bovine genome but vary in extent between tissues. However, even when the height of a peak was positively correlated across tissues with expression of an exon, ASE of the exon and ASB of the peak were in the same direction only half the time. A likely explanation for this finding is that the correlations between peak height and exon expression do not indicate that the height of the peak causes the extent of exon expression, at least in some cases., (© 2023. Springer Nature Limited.)

Human endometrial stromal cells (hESCs) undergo a differentiation process with dramatic changes in cell functions during the menstrual cycle, which is called decidualization. This is an important event for implantation of the embryo and successful pregnancy. Defective decidualization can cause implantation failure, miscarriage, and unexplained infertility. A number of genes are upregulated or downregulated during decidualization. Recent studies have shown that epigenetic mechanisms are involved in the regulation of decidualization-related genes and that histone modifications occur throughout the genome during decidualization. The present review focuses on the involvement of genome-wide histone modifications in dramatic changes in gene expression during decidualization. The main histone modifications are the increases of H3K27ac and H3K4me3, which activate transcription. C/EBPβ works as a pioneer factor throughout the genome by recruiting p300. This is the main cause of the genome-wide acetylation of H3K27 during decidualization. Histone modifications were observed in both the proximal promoter and distal enhancer regions. Genome editing experiments show that the distal regions have transcriptional activities, which suggests that decidualization induces the interactions between proximal promoter and distal enhancer regions. Taken together, these findings show that gene regulation during decidualization is closely associated with genome-wide changes of histone modifications. This review provides new insights regarding the cases of implantation failure in terms of decidualization insufficiency owing to epigenetic dysregulation, and may lead to novel treatment options for women with implantation failure., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pulmonary hypertension is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular failure, and premature death. It is a threat to public health globally. Autophagy, as a highly conserved self-digestion process, plays crucial roles with autophagy-related (ATG) proteins in various diseases. The components of autophagy in the cytoplasm have been studied for decades and multiple studies have provided evidence of the importance of autophagic dysfunction in pulmonary hypertension. The status of autophagy plays a dynamic suppressive or promotive role in different contexts and stages of pulmonary hypertension development. Although the components of autophagy have been well studied, the molecular basis for the epigenetic regulation of autophagy is less understood and has drawn increasing attention in recent years. Epigenetic mechanisms include histone modifications, chromatin modifications, DNA methylation, RNA alternative splicing, and non-coding RNAs, which control gene activity and the development of an organism. In this review, we summarize the current research progress on epigenetic modifications in the autophagic process, which have the potential to be crucial and powerful therapeutic targets against the autophagic process in pulmonary hypertension development., Competing Interests: Author JiL was employed by companies Shenzhen Reyson Biotechnology Co., Ltd. and Nanjing Evertop Electronics Ltd. Author WZ was employed by company NCPC Hebei Huamin Pharmaceutical Co., Ltd. The remaining 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 Mao, Song, Li, Lu, Li, Zhao, Liu, Liu and Zeng.)

Histone modifications play crucial roles in the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury. However, a genome-wide map of histone modifications and the underlying epigenetic signatures in myocardial I/R injury have not been established. Here, we integrated transcriptome and epigenome of histone modifications to characterize epigenetic signatures after I/R injury. Disease-specific histone mark alterations were mainly found in H3K27me3-, H3K27ac-, and H3K4me1-marked regions 24 and 48 h after I/R. Genes differentially modified by H3K27ac, H3K4me1 and H3K27me3 were involved in immune response, heart conduction or contraction, cytoskeleton, and angiogenesis. H3K27me3 and its methyltransferase polycomb repressor complex 2 (PRC2) were upregulated in myocardial tissues after I/R. Upon selective inhibition of EZH2 (the catalytic core of PRC2), the mice manifest improved cardiac function, enhanced angiogenesis, and reduced fibrosis. Further investigations confirmed that EZH2 inhibition regulated H3K27me3 modification of multiple pro-angiogenic genes and ultimately enhanced angiogenic properties in vivo and in vitro. This study delineates a landscape of histone modifications in myocardial I/R injury, and identifies H3K27me3 as a key epigenetic modifier in I/R process. The inhibition of H3K27me3 and its methyltransferase might be a potential strategy for myocardial I/R injury intervention., (© 2023. Science China Press.)

Regulation of chromatin states involves the dynamic interplay between different histone modifications to control gene expression. Recent advances have enabled mapping of histone marks in single cells, but most methods are constrained to profile only one histone mark per cell. Here, we present an integrated experimental and computational framework, scChIX-seq (single-cell chromatin immunocleavage and unmixing sequencing), to map several histone marks in single cells. scChIX-seq multiplexes two histone marks together in single cells, then computationally deconvolves the signal using training data from respective histone mark profiles. This framework learns the cell-type-specific correlation structure between histone marks, and therefore does not require a priori assumptions of their genomic distributions. Using scChIX-seq, we demonstrate multimodal analysis of histone marks in single cells across a range of mark combinations. Modeling dynamics of in vitro macrophage differentiation enables integrated analysis of chromatin velocity. Overall, scChIX-seq unlocks systematic interrogation of the interplay between histone modifications in single cells., (© 2023. The Author(s).)

In eukaryotes, the combination of different histone post-translational modifications (PTMs) - the histone code - impacts the chromatin organization as compact and transcriptionally silent heterochromatin or accessible and transcriptionally active euchromatin. Although specific histone PTMs have been studied in fungi, an overview of histone PTMs and their relative abundance is still lacking. Here, we used mass spectrometry to detect and quantify histone PTMs in three fungal species belonging to three distinct taxonomic sections of the genus Aspergillus (Aspergillus niger, Aspergillus nidulans (two strains), and Aspergillus fumigatus). We overall detected 23 different histone PTMs, including a majority of lysine methylations and acetylations, and 23 co-occurrence patterns of multiple histone PTMs. Among those, we report for the first time the detection of H3K79me1, H3K79me2, and H4K31ac in Aspergilli. Although all three species harbour the same PTMs, we found significant differences in the relative abundance of H3K9me1/2/3, H3K14ac, H3K36me1 and H3K79me1, as well as the co-occurrence of acetylation on both K18 and K23 of histone H3 in a strain-specific manner. Our results provide novel insights about the underexplored complexity of the histone code in filamentous fungi, and its functional implications on genome architecture and gene regulation., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Histone modification is an important epigenetic regulatory mechanism and essential for stress adaptation in plants. However, systematic analysis of histone modification genes (HMs) in Brassicaceae species is lacking, and their roles in response to abiotic stress have not yet been identified., Results: In this study, we identified 102 AtHMs, 280 BnaHMs, 251 BcHMs, 251 BjHMs, 144 BnHMs, 155 BoHMs, 137 BrHMs, 122 CrHMs, and 356 CsHMs in nine Brassicaceae species, respectively. Their chromosomal locations, protein/gene structures, phylogenetic trees, and syntenies were determined. Specific domains were identified in several Brassicaceae HMs, indicating an association with diverse functions. Syntenic analysis showed that the expansion of Brassicaceae HMs may be due to segmental and whole-genome duplications. Nine key BnaHMs in allotetraploid rapeseed may be responsible for ammonium, salt, boron, cadmium, nitrate, and potassium stress based on co-expression network analysis. According to weighted gene co-expression network analysis (WGCNA), 12 BnaHMs were associated with stress adaptation. Among the above genes, BnaPRMT11 simultaneously responded to four different stresses based on differential expression analysis, while BnaSDG46, BnaHDT10, and BnaHDA1 participated in five stresses. BnaSDG46 was also involved in four different stresses based on WGCNA, while BnaSDG10 and BnaJMJ58 were differentially expressed in response to six different stresses. In summary, six candidate genes for stress resistance (BnaPRMT11, BnaSDG46, BnaSDG10, BnaJMJ58, BnaHDT10, and BnaHDA1) were identified., Conclusions: Taken together, these findings help clarify the biological roles of Brassicaceae HMs. The identified candidate genes provide an important reference for the potential development of stress-tolerant oilseed plants., (© 2023. The Author(s).)

Heterogeneous nuclear ribonucleoprotein K (HNRNPK, hnRNP K), a multifunctional RNA/DNA binding protein, mainly regulates transcription, translation and RNA splicing, and then plays oncogenic roles in many cancers. However, the related mechanisms remain largely unknown. Here, we found that HNRNPK can partially epigenetically regulate cancer cell proliferation via increasing transcription and exon 4-inclusion of SPIN1, an important oncogenic histone code reader. This exon 4 skipping event of SPIN1 generates a long non-coding RNA, followed by the downregulation of SPIN1 protein. SPIN1 is one of the most significantly co-expressed genes of HNRNPK in thirteen TCGA cancers. Our further studies revealed HNRNPK knockdown significantly inhibited cell growth and cell cycle progression in oral squamous cell carcinoma (OSCC) cells and promoted cell apoptosis. Overexpression of SPIN1 was able to partially rescue the growth inhibition triggered by HNRNPK knockdown. Moreover, CCND1 (Cyclin D1), a key cell cycle regulator and oncogene, epigenetically up-regulated by SPIN1, was also positively regulated by HNRNPK. In addition, we discovered that HNRNPK promoted SPIN1 exon 4 inclusion by interacting with an intronic splicing enhancer in intron 4. Collectively, our study suggests a novel epigenetic regulatory pathway of HNRNPK in OSCC, mediated by controlling the transcription activity and alternative splicing of SPIN1 gene., 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 Ltd. All rights reserved.)

Sepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between hyperinflammation and immunosuppression is a crucial feature of sepsis immunity. Epigenetic modifications, including histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA, play essential roles in regulating sepsis immunity through epi-information independent of the DNA sequence. In recent years, the mechanisms of histone modification in sepsis have received increasing attention, with ongoing discoveries of novel types of histone modifications. Due to the capacity for prolonged effects on immune cells, histone modifications can induce immune cell reprogramming and participate in the long-term immunosuppressed state of sepsis. Herein, we systematically review current mechanisms of histone modifications involved in the regulation of sepsis, summarize their role in sepsis from an immune perspective and provide potential therapeutic opportunities targeting histone modifications in sepsis treatment., (© 2023. The Author(s).)

Predicting differential gene expression (DGE) from Histone modifications (HM) signal is crucial to understand how HM controls cell functional heterogeneity through influencing differential gene regulation. Most existing prediction methods use fixed-length bins to represent HM signals and transmit these bins into a single machine learning model to predict differential expression genes of single cell type or cell type pair. However, the inappropriate bin length may cause the splitting of the important HM segment and lead to information loss. Furthermore, the bias of single learning model may limit the prediction accuracy. Considering these problems, in this paper, we proposes an Ensemble deep neural networks framework for predicting Differential Gene Expression (EnDGE). EnDGE employs different feature extractors on input HM signal data with different bin lengths and fuses the feature vectors for DGE prediction. Ensemble multiple learning models with different HM signal cutting strategies helps to keep the integrity and consistency of genetic information in each signal segment, and offset the bias of individual models. Besides the popular feature extractors, we also propose a new Residual Network based model with higher prediction accuracy to increase the diversity of feature extractors. Experiments on the real datasets from the Roadmap Epigenome Project (REMC) show that for all cell type pairs, EnDGE significantly outperforms the state-of-the-art baselines for differential gene expression prediction.

Introduction: SOX2 plays a crucial role in tumor development, cancer stem cell maintenance, and cancer progression. Mechanisms of SOX2 gene regulation in human breast and prostate cancers are not established yet., Methods: SOX2 expression in prostate and breast cancer tissues and cell lines was determined by qRT-PCR, Western blot, and immunochemistry, followed by the investigation of pro-tumorigenic properties like cell proliferation, migration, and apoptosis by gene knockdown and treatment with epigenetic modulators and ChIP., Results: Prostate and breast cancer tissues showed very high expression of SOX2. All cancer cell lines DU145 and PC3 (prostate) and MCF7 and MDA-MB-231 (breast) exhibited high expression of SOX2. Inhibition of SOX2 drastically decreased cell proliferation and migration. Epigenetic modulators enhanced SOX2 gene expression in both cancer types. DNA methylation pattern in SOX2 promoter could not be appreciably counted for SOX2 overexpression. Activation of SOX2 gene promoter was due to very high deposition of H3K4me3 and H3K9acS10p and drastic decrease of H3K9me3 and H3K27me3., Conclusion: Histone modification is crucial for the overexpression of SOX2 during tumor development and cancer progression. These findings show the avenue of co-targeting SOX2 and its active epigenetic modifier enzymes to effectively treat aggressive prostate and breast cancers., (© 2023 S. Karger AG, Basel.)

The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome., (© 2022. The Author(s).)

Epigenetic regulation, mainly involving DNA methylation, histone modification, and noncoding RNAs (ncRNAs), is essential for the regulation of multiple cellular processes. Dental-derived mesenchymal stem cells (DMSCs), a kind of multipotent cells derived from dental tissues, are impactful in regenerative medicine. Recent studies have shown that epigenetic regulation plays a major role in DMSCs. Therefore, exploring how epigenetic regulation is involved in DMSCs may be of guiding significance for tissue repair and regeneration or for exploring more effective treatments. A number of research of ncRNAs in DMSCs have been reported. However, little is known about the roles of DNA methylation and histone modifications in DMSCs. In this review, we summarize the important roles of DNA methylation and histone modifications of the fate of DMSCs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We recently adapted a CUT&RUN protocol for genome-wide profiling of chromatin modifications in the human malaria parasite Plasmodium Using the step-by-step protocol described below, we were able to generate high-quality profiles of multiple histone modifications using only a small fraction of the cells required for ChIP-seq. Using antibodies against two commonly profiled histone modifications, H3K4me3 and H3K9me3, we show here that CUT&RUN profiling is highly reproducible and closely recapitulates previously published ChIP-seq-based abundance profiles of histone marks. Finally, we show that CUT&RUN requires substantially lower sequencing coverage for accurate profiling compared with ChIP-seq., (© 2022 Morillo et al.)

The quantitative characterization of the transcriptional control by histone modifications has been challenged by many computational studies, but most of them only focus on narrow and linear genomic regions around promoters, leaving a room for improvement. We present Chromoformer, a transformer-based, three-dimensional chromatin conformation-aware deep learning architecture that achieves the state-of-the-art performance in the quantitative deciphering of the histone codes in gene regulation. The core essence of Chromoformer architecture lies in the three variants of attention operation, each specialized to model individual hierarchy of transcriptional regulation involving from core promoters to distal elements in contact with promoters through three-dimensional chromatin interactions. In-depth interpretation of Chromoformer reveals that it adaptively utilizes the long-range dependencies between histone modifications associated with transcription initiation and elongation. We also show that the quantitative kinetics of transcription factories and Polycomb group bodies can be captured by Chromoformer. Together, our study highlights the great advantage of attention-based deep modeling of complex interactions in epigenomes., (© 2022. The Author(s).)

Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle., (© 2022 Pillon et al.)

Background : Periodontitis is a chronic inflammatory disease involving an interplay between bacteria, inflammation, host response genes, and environmental factors. The manifestation of epigenetic factors during periodontitis pathogenesis and periodontal inflammation is still not well understood, with limited reviews on histone modification with periodontitis management. This scoping review aims to evaluate current evidence of global and specific DNA methylation and histone modification in periodontitis and discuss the gaps and implications for future research and clinical practice. Methods : A scoping literature search of three electronic databases was performed in SCOPUS, MEDLINE (PubMed) and EMBASE. As epigenetics in periodontitis is an emerging research field, a scoping review was conducted to identify the extent of studies available and describe the overall context and applicability of these results. Results : Overall, 30 studies were evaluated, and the findings confirmed that epigenetic changes in periodontitis comprise specific modifications to DNA methylation patterns and histone proteins modification, which can either dampen or promote the inflammatory response to bacterial challenge. Conclusions : The plasticity of epigenetic modifications has implications for the future development of targeted epi-drugs and diagnostic tools in periodontitis. Such advances could be invaluable for the early detection and monitoring of susceptible individuals., Competing Interests: The authors declare no conflict of interest.

Chemical modifications of DNA and histone proteins impact the organization of chromatin within the nucleus. Changes in these modifications, catalysed by different chromatin-modifying enzymes, influence chromatin organization, which in turn is thought to impact the spatial and temporal regulation of gene expression. While combinations of different histone modifications, the histone code, have been studied in several model species, we know very little about histone modifications in the fungal genus Aspergillus , whose members are generally well studied due to their importance as models in cell and molecular biology as well as their medical and biotechnological relevance. Here, we used phylogenetic analyses in 94 Aspergilli as well as other fungi to uncover the occurrence and evolutionary trajectories of enzymes and protein complexes with roles in chromatin modifications or regulation. We found that these enzymes and complexes are highly conserved in Aspergilli, pointing towards a complex repertoire of chromatin modifications. Nevertheless, we also observed few recent gene duplications or losses, highlighting Aspergillus species to further study the roles of specific chromatin modifications. SET7 (KMT6) and other components of PRC2 (Polycomb Repressive Complex 2), which is responsible for methylation on histone H3 at lysine 27 in many eukaryotes including fungi, are absent in Aspergilli as well as in closely related Penicillium species, suggesting that these lost the capacity for this histone modification. We corroborated our computational predictions by performing untargeted MS analysis of histone post-translational modifications in Aspergillus nidulans . This systematic analysis will pave the way for future research into the complexity of the histone code and its functional implications on genome architecture and gene regulation in fungi.

Early embryos undergo extensive epigenetic reprogramming to achieve gamete-to-embryo transition, which involves the loading and removal of histone variant H2A.Z on chromatin. However, how does H2A.Z regulate gene expression and histone modifications during preimplantation development remains unrevealed. Here, by using ultra-low-input native chromatin immunoprecipitation and sequencing, the genome-wide distribution of H2A.Z is delineated in mouse oocytes and early embryos. These landscapes indicate that paternal H2A.Z is removed upon fertilization, followed by unbiased accumulation on parental genomes during zygotic genome activation (ZGA). Remarkably, H2A.Z exhibits hierarchical accumulation as different peak types at promoters: promoters with double H2A.Z peaks are colocalized with H3K4me3 and indicate transcriptional activation; promoters with a single H2A.Z peak are more likely to occupy bivalent marks (H3K4me3+H3K27me3) and indicate development gene suppression; promoters with no H2A.Z accumulation exhibit persisting gene silencing in early embryos. Moreover, H2A.Z depletion changes the enrichment of histone modifications and RNA polymerase II binding at promoters, resulting in abnormal gene expression and developmental arrest during lineage commitment. Furthermore, similar transcription and accumulation patterns between mouse and porcine embryos indicate that a dual role of H2A.Z in regulating the epigenome required for proper gene expression is conserved during mammalian preimplantation development., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Alternative splicing (AS) is a tightly regulated mechanism that generates the complex human proteome from a small number of genes. Cis -regulatory RNA motifs in exons and introns control AS, recruiting positive and negative trans -acting splicing regulators. At a higher level, chromatin affects splicing events. Growing evidence indicates that the popular histone code hypothesis can be extended to RNA-level processes, such as AS. In addition to nucleosome positioning, which can generate transcriptional barriers to shape the final splicing outcome, histone post-translational modifications can contribute to the detailed regulation of single exon inclusion/exclusion. A histone-based system can identify alternatively spliced chromatin stretches, affecting RNAPII elongation locally or recruiting splicing components via adaptor complexes. In tumor cells, several mechanisms trigger misregulated AS events and produce cancer-associated transcripts. On a genome-wide level, aberrant AS can be the consequence of dysfunctional epigenetic splicing code, including altered enrichment in histone post-translational modifications. This review describes the main findings related to the effect of histone modifications and variants on splicing outcome and how a dysfunctional epigenetic splicing code triggers aberrant AS in cancer. In addition, it highlights recent advances in programmable DNA-targeting technologies and their possible application for AS targeted epigenetic modulation.

Individual analysis of the epigenome of preimplantation embryos is useful for characterizing each embryo and for investigating the effects of environmental factors on their epigenome. However, it is difficult to analyze genome-wide epigenetic modifications, especially histone modifications, in a large number of single embryos due to the small number of cells and the complexity of the analysis methods. To solve this problem, we further modified the CUT&Tag method, which can analyze histone modifications in a small number of cells, such that the embryo is handled as a cell mass in the reaction solutions in the absence of the solid-phase magnetic beads that are used for antibody and enzyme reactions in the conventional method (NON-TiE-UP CUT&Tag; NTU-CAT). By using bovine blastocysts as a model, we showed that genome-wide profiles of representative histone modifications, H3K4me3 and H3K27me3, could be obtained by NTU-CAT that are in overall agreement with the conventional chromatin immunoprecipitation-sequencing (ChIP-seq) method, even from single embryos. However, this new approach has limitations that require attention, including false positive and negative peaks and lower resolution for broad modifications. Despite these limitations, we consider NTU-CAT a promising replacement for ChIP-seq with the great advantage of being able to analyze individual embryos., (© 2022. The Author(s).)

Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided., (© 2022. The Author(s).)

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation., Competing Interests: JL, AP, MZ, MC, CL, JO, LF, CL, JL, RG, JN, IS, YP, TS, SP, JE, EM, MB No competing interests declared, (© 2022, Li, Pinto-Duarte et al.)

Parathyroid tumors are very prevalent conditions among endocrine tumors, being the second most common behind thyroid tumors. Secondary hyperplasia can occur beyond benign and malignant neoplasia in parathyroid glands. Adenomas are the leading cause of hyperparathyroidism, while carcinomas represent less than 1% of the cases. Tumor suppressor gene mutations such as MEN1 and CDC73 were demonstrated to be involved in tumor development in both familiar and sporadic types; however, the epigenetic features of the parathyroid tumors are still a little-explored subject. We present a review of epigenetic mechanisms related to parathyroid tumors, emphasizing advances in histone modification and its perspective of becoming a promising area in parathyroid tumor research.

Genome regulation is governed by the dynamics of chromatin modifications. The extensive and diverse array of DNA and histone modifications allow multiple elements to act combinatorically and direct tissue-specific and cell-specific outcomes. Yet, our ability to elucidate these complex combinations and link them to normal genome regulation, as well as understand their deregulation in cancer, has been hindered by the lack of suitable technologies. Here, we describe recent findings indicating the importance of the combinatorial epigenome, and novel methodologies to measure and characterize these combinations. These complementary methods span multiple disciplines, providing a means to decode epigenetic combinations and link them to biological outcomes. Finally, we discuss the promise of harnessing the rich combinatorial epigenetic information to improve cancer diagnostics and monitoring., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The role of histone modifications in transcription remains incompletely understood. Here, we examine the relationship between histone modifications and transcription using experimental perturbations combined with sensitive machine-learning tools. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3, consistent with a role for RNA in recruiting PRC2. A subset of DNase-I-hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than an essential regulatory, role in transcription., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

During cell devision, maintaining the epigenetic information encoded in histone modification patterns is crucial for survival and identity of cells. The faithful inheritance of the histone marks from the parental to the daughter strands is a puzzle, given that each strand gets only half of the parental nucleosomes. Mapping DNA replication and reconstruction of modifications to equivalent problems in communication of information, we ask how well enzymes can recover the parental modifications, if they were ideal computing machines. Studying a parameter regime where realistic enzymes can function, our analysis predicts that enzymes may implement a critical threshold filling algorithm which fills unmodified regions of length at most k. This algorithm, motivated from communication theory, is derived from the maximum à posteriori probability (MAP) decoding which identifies the most probable modification sequence based on available observations. Simulations using our method produce modification patterns similar to what has been observed in recent experiments. We also show that our results can be naturally extended to explain inheritance of spatially distinct antagonistic modifications., Competing Interests: The authors have declared that no competing interests exist.

Histone modifications impact final splicing decisions. However, there is little evidence of the driving role of these marks in inducing cell-specific splicing changes. Using CRISPR epigenome editing tools, we show in an epithelial-to-mesenchymal cell reprogramming system (epithelial-to-mesenchymal transition [EMT]) that a single change in H3K27ac or H3K27me3 levels right at the alternatively spliced exon is necessary and sufficient to induce a splicing change capable of recapitulating important aspects of EMT, such as cell motility and invasiveness. This histone-mark-dependent splicing effect is highly dynamic and mediated by direct recruitment of the splicing regulator PTB to its RNA binding sites. These results support a role for H3K27 marks in inducing a change in the cell's phenotype via regulation of alternative splicing. We propose the dynamic nature of chromatin as a rapid and reversible mechanism to coordinate the splicing response to cell-extrinsic cues, such as induction of EMT., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

R-loop, a three-stranded RNA/DNA structure, plays important roles in modulating genome stability and gene expression, but the molecular mechanism of R-loops in cell reprogramming remains elusive. Here, we comprehensively profiled the genome-wide landscape of R-loops during cell reprogramming. The results showed that the R-loop formation on most different types of repetitive elements is stage-specific in cell reprogramming. We unveiled that the cumulative deposition of an R-loop subset is positively correlated with gene expression during reprogramming. More importantly, the dynamic turnover of this R-loop subset is accompanied by the activation of the pluripotent transcriptional regulatory network (TRN). Moreover, the large accumulation of the active histone marker H3K4me3 and the reduction in H3K27me3 were also observed in these R-loop regions. Finally, we characterized the dynamic network of R-loops that facilitates cell fate transitions in reprogramming. Together, our study provides a new clue for deciphering the interplay mechanism between R-loops and HMs to control cell reprogramming.

Graves' Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves' disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome., 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 Wang, Ma, Wang, Sun, Wang, Li, Liu and Yu.)

Background: Oil palm (Elaeis guineensis, Jacq.) is an important vegetable oil-yielding plant. Somatic embryogenesis is a promising method to produce large-scale elite clones to meet the demand for palm oil. The epigenetic mechanisms such as histone modifications have emerged as critical factors during somatic embryogenesis. These histone modifications are associated with the regulation of various genes controlling somatic embryogenesis. To date, none of the information is available on the histone modification gene (HM) family in oil palm., Results: We reported the identification of 109 HM gene family members including 48 HMTs, 27 HDMs, 13 HATs, and 21 HDACs in the oil palm genome. Gene structural and motif analysis of EgHMs showed varied exon-intron organization and with conserved motifs among them. The identified 109 EgHMs were distributed unevenly across 16 chromosomes and displayed tandem duplication in oil palm genome. Furthermore, relative expression analysis showed the differential expressional pattern of 99 candidate EgHM genes at different stages (non-embryogenic, embryogenic, somatic embryo) of somatic embryogenesis process in oil palm, suggesting the EgHMs play vital roles in somatic embryogenesis. Our study laid a foundation to understand the regulatory roles of several EgHM genes during somatic embryogenesis., Conclusions: A total of 109 histone modification gene family members were identified in the oil palm genome via genome-wide analysis. The present study provides insightful information regarding HM gene's structure, their distribution, duplication in oil palm genome, and also their evolutionary relationship with other HM gene family members in Arabidopsis and rice. Finally, our study provided an essential role of oil palm HM genes during somatic embryogenesis process., (© 2021. The Author(s).)

Cereals are important crops and are exposed to various types of environmental stresses that affect the overall growth and yield. Among the various abiotic stresses, salt stress is a major environmental factor that influences the genetic, physiological, and biochemical responses of cereal crops. Epigenetic regulation which includes DNA methylation, histone modification, and chromatin remodelling plays an important role in salt stress tolerance. Recent studies in rice genomics have highlighted that the epigenetic changes are heritable and therefore can be considered as molecular signatures. An epigenetic mechanism under salinity induces phenotypic responses involving modulations in gene expression. Association between histone modification and altered DNA methylation patterns and differential gene expression has been evidenced for salt sensitivity in rice and other cereal crops. In addition, epigenetics also creates stress memory that helps the plant to better combat future stress exposure. In the present review, we have discussed epigenetic influences in stress tolerance, adaptation, and evolution processes. Understanding the epigenetic regulation of salinity could help for designing salt-tolerant varieties leading to improved crop productivity., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes., (© 2021. The Author(s).)

It remains a challenge to decipher the complex relationship between DNA methylation, histone modification, and the underlying DNA sequence with limited input material. Here, we developed an efficient, low-input, and low-cost method for the simultaneous profiling of genomic localization of histone modification and methylation status of the underlying DNA at single-base resolution from the same cells in a single experiment by integrating cleavage under targets and tagmentation (CUT&Tag) with tagmentation-based bisulfite sequencing (CUT&Tag-BS). We demonstrated the validity of our method using representative histone modifications of euchromatin and constitutive and facultative heterochromatin (H3K4me1, H3K9me3, and H3K27me3, respectively). Similar histone modification enrichment patterns were observed in CUT&Tag-BS compared with non-bisulfite-treated control, and H3K4me1-marked regions were found to mostly be CpG poor, lack methylation concordance, and exhibit prevalent DNA methylation heterogeneity among mouse embryonic stem cells (mESCs). We anticipate that CUT&Tag-BS will be widely applied to directly address the genomic relationship between DNA methylation and histone modification, especially in low-input scenarios with precious biological samples., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that often occurs concurrently with frontotemporal dementia (FTD), another disorder involving progressive neuronal loss. ALS and FTD form a neurodegenerative continuum and share pathological and genetic features. Mutations in a multitude of genes have been linked to ALS/FTD, including FUS. The FUS protein aggregates and forms inclusions within affected neurons. However, the precise mechanisms connecting protein aggregation to neurotoxicity remain under intense investigation. Recent evidence points to the contribution of epigenetics to ALS/FTD. A main epigenetic mechanism involves the post-translational modification (PTM) of histone proteins. We have previously characterized the histone PTM landscape in a FUS ALS/FTD yeast model, finding a decreased level of acetylation on lysine residues 14 and 56 of histone H3. Here, we describe the first report of amelioration of disease phenotypes by controlling histone acetylation on specific modification sites. We show that inhibiting histone deacetylases, via treatment with trichostatin A, suppresses the toxicity associated with FUS overexpression in yeast by preserving the levels of H3K56ac and H3K14ac without affecting the expression or aggregation of FUS. Our data raise the novel hypothesis that the toxic effect of protein aggregation in neurodegeneration is related to its association with altered histone marks. Altogether, we demonstrate the ability to counter the repercussions of protein aggregation on cell survival by preventing specific histone modification changes. Our findings launch a novel mechanistic framework that will enable alternative therapeutic approaches for ALS/FTD and other neurodegenerative diseases.

Genome-wide association studies (GWASs) have identified more than 200 prostate cancer (PrCa) risk regions, which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues, thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirm previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g., MLPH). Interestingly, HiChIP identifies links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g., AR) that are not detected by eQTL-based methods. HiChIP predicted enhancer elements at the AR and NKX3-1 prostate cancer risk loci, and both were experimentally confirmed to regulate expression of the corresponding genes through CRISPR interference (CRISPRi) perturbation in LNCaP cells. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.