Covalent Histone Modifications Research Articles

RNA-seq-based elucidation of lactylation in breast cancer

IntroductionLactylation is the covalent modification of histones using lactate as a small molecule precursor, playing a role in epigenetic regulation. As a novel protein post-translational modification, it has demonstrated significant relevance in the field of cancer diagnosis and therapy. However, the interaction between lactylation and tumor cells in breast cancer has not been extensively investigated.Material and methodsWe acquired breast cancer-related data from the GEO and TCGA databases. Lactylation-related genes were identified from the differentially expressed genes. We utilized COX and LASSO regression to identify genes with significant prognostic value for constructing a prognostic model and assessing its predictive performance. This model was integrated with clinical parameters to create a nomogram. Finally, we conducted immune infiltration analysis, analyzed differences in biological functions, and assessed drug sensitivity.ResultsWe ultimately identified 3 lactylation-related genes significantly associated with prognosis. These genes were used to construct a prognostic model and calculate a risk score. Using the median score, patients were divided into high-risk and low-risk groups. Notably, the low-risk group patients exhibited better prognosis and higher levels of immune infiltration. GO/KEGG enrichment analysis revealed that PGK1, the gene with the highest HR among these genes, is widely involved in immune, metabolic, and proliferative signaling pathways. Its high expression also correlates with increased sensitivity to anti-tumor drugs.ConclusionsWe showcased the potential of lactylation-based molecular clustering and prognostic profiling for predicting survival, immune status, and treatment response in breast cancer patients. Additionally, we envision the utilization of PGK1 as a diagnostic marker and therapeutic target in the cancer.

A critical role for Pol II CTD phosphorylation in heterochromatic gene activation

How gene activation works in heterochromatin, and how the mechanism might differ from the one used in euchromatin, has been largely unexplored. Previous work has shown that in SIR-regulated heterochromatin of Saccharomyces cerevisiae, gene activation occurs in the absence of covalent histone modifications and other alterations of chromatin commonly associated with transcription.Here we demonstrate that such activation occurs in a substantial fraction of cells, consistent with frequent transcriptional bursting, and this raises the possibility that an alternative activation pathway might be used. We address one such possibility, Pol II CTD phosphorylation, and explore this idea using a natural telomere-linked gene, YFR057w, as a model. Unlike covalent histone modifications, we find that Ser2, Ser5 and Ser7 CTD phosphorylated Pol II is prevalent at the drug-induced heterochromatic gene. Particularly enriched relative to the euchromatic state is Ser2 phosphorylation. Consistent with a functional role for Ser2P, YFR057w is negligibly activated in cells deficient in the Ser2 CTD kinases Ctk1 and Bur1 even though the gene is strongly stimulated when it is placed in a euchromatic context. Collectively, our results are consistent with a critical role for Ser2 CTD phosphorylation in driving Pol II recruitment and transcription of a natural heterochromatic gene – an activity that may supplant the need for histone epigenetic modifications.

Automated ChIPmentation procedure on limited biological material of the human blood fluke Schistosoma mansoni

In living cells, the genetic information stored in the DNA sequence is always associated with chromosomal and extra-chromosomal epigenetic information. Chromatin is formed by the DNA and associated proteins, in particular histones. Covalent histone modifications are important bearers of epigenetic information and as such have been increasingly studied since about the year 2000. One of the principal techniques to gather information about the association between DNA and modified histones is chromatin immunoprecipitation (ChIP), also combined with massive sequencing (ChIP-Seq). Automated ChIPmentation procedure is a convenient alternative to native chromatin immunoprecipitation (N-ChIP). It is now routinely used for ChIP-Seq in many model species, using in general roughly 106 cells per experiment. Such high cell numbers are sometimes difficult to produce. Using the human parasite Schistosoma mansoni, whose production requires sacrificing animals and should therefore be kept to a minimum, we show here that automated ChIPmentation is suitable for limited biological material. We define the operational limit as ≥20,000 Schistosoma cells with 30,000-300,000 cells as optimum. We also present a streamlined protocol for the preparation of ChIP input libraries.

Vitamin D and the epigenome: basic definitions, mechanisms and clinical effects

Epigenetic mechanisms play a crucial role in the regulation of gene expression. The underlying mechanisms include DNA methylation and covalent modification of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of various epigenetic mechanisms is mediated by enzymes operating in the cell nucleus. Modifications in DNA methylation are carried out primarily by DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs), while a variety of enzymes such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs)) regulate histone covalent modifications. In many pathological conditions such as cancer, autoimmune, microbial inflammatory, metabolic, allergic diseases and/or low vitamin D availability, the epigenetic regulatory system is often disrupted. Vitamin D interacts with the epigenome at several levels. First, critical genes in the vitamin D signaling system that encode for the vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoters. areas and therefore can be suppressed by DNA methylation. Second, the VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers such as HATs, HDACs, HMTS, and chromatin remodelers. Third, a number of genes encoding chromatin modifiers and remodelers, such as HDM from the Jumonji C (JmjC) domain containing proteins and lysine-specific demethylase (LSD) families, are primary targets for VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review, the authors discuss the regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome and assess its impact on health and disease.

The role of epigenetic and epitranscriptomic modifications in plants exposed to non-essential metals.

Contamination of the soil with non-essential metals and metalloids is a serious problem in many regions of the world. These non-essential metals and metalloids are toxic to all organisms impacting crop yields and human health. Crop plants exposed to high concentrations of these metals leads to perturbed mineral homeostasis, decreased photosynthesis efficiency, inhibited cell division, oxidative stress, genotoxic effects and subsequently hampered growth. Plants can activate epigenetic and epitranscriptomic mechanisms to maintain cellular and organism homeostasis. Epigenetic modifications include changes in the patterns of cytosine and adenine DNA base modifications, changes in cellular non-coding RNAs, and remodeling histone variants and covalent histone tail modifications. Some of these epigenetic changes have been shown to be long-lasting and may therefore contribute to stress memory and modulated stress tolerance in the progeny. In the emerging field of epitranscriptomics, defined as chemical, covalent modifications of ribonucleotides in cellular transcripts, epitranscriptomic modifications are postulated as more rapid modulators of gene expression. Although significant progress has been made in understanding the plant's epigenetic changes in response to biotic and abiotic stresses, a comprehensive review of the plant's epigenetic responses to metals is lacking. While the role of epitranscriptomics during plant developmental processes and stress responses are emerging, epitranscriptomic modifications in response to metals has not been reviewed. This article describes the impact of non-essential metals and metalloids (Cd, Pb, Hg, Al and As) on global and site-specific DNA methylation, histone tail modifications and epitranscriptomic modifications in plants.

Ubiquitin-proteasome system regulation of a key gene regulatory factor, Paf1C

Paf1 (Polymerase-associated factor 1) complex (Paf1C) is evolutionarily conserved from yeast to humans, and facilitates transcription elongation as well as co-transcriptional histone covalent modifications and mRNA 3’-end processing. Thus, Paf1C is a key player in regulation of eukaryotic gene expression. Paf1C consists of Paf1, Cdc73, Ctr9, Leo1 and Rtf1 in both yeast and humans, but it has an additional component, Ski8, in humans. The abundances of these components regulate the assembly of Paf1C and/or its functions, thus implying the mechanisms involved in regulating the abundances of the Paf1C components in altered gene expression and hence cellular pathologies. Towards finding the mechanisms associated with the abundances of the Paf1C components, we analyzed here whether the Paf1C components are regulated via targeted ubiquitylation and 26S proteasomal degradation. We find that the Paf1C components except Paf1 do not undergo the 26S proteasomal degradation in both yeast and humans. Paf1 is found to be regulated by the ubiquitin-proteasome system (UPS) in yeast and humans. Alteration of such regulation changes Paf1’s abundance, leading to aberrant gene expression. Intriguingly, while the Rtf1 component of Paf1C does not undergo the 26S proteasomal degradation, it is found to be ubiquitylated, suggesting that Rtf1 ubiquitylation could be engaged in Paf1C assembly and/or functions. Collectively, our results reveal distinct UPS regulation of the Paf1C components, Paf1 and Rtf1, in a proteolysis-dependent and -independent manners, respectively, with functional implications.

Understanding and Targeting the Epigenetic Regulation to Overcome EGFR-TKIs Resistance in Human Cancer.

The occurrence and progression of cancer are the results of the dysregulation of genetics and epigenetics. Epigenetic regulation can reversibly affect gene transcription activity without changing DNA structure. Covalent modification of histones is crucial in the epigenetic regulation of gene expression. Furthermore, epidermal growth factor receptor (EGFR) significantly affects cell tumorigenesis, proliferation, antitumor drug resistance, etc. Overexpression of EGFR promotes cancer development. Therefore, EGFR-targeted drugs have become the focus of tumor therapy. With the advent of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), EGFR-TKIs resistance, which occurs about half a year to a year, has become an obstacle in cancer treatment. The objective of this study is to discuss the ways to overcome EGFR-TKIs resistance in a variety of tumors. The combination therapy of epigenetic drugs and other drugs is used. The combination of the two drugs can overcome the resistance of EGFR-TKIs and prolong the survival of patients. This article depicts the concepts of epigenetics and the mechanism of EGFR-TKIs resistance and then illustrates the relationship between epigenetic mechanisms and EGFR-TKIs resistance. Finally, it discusses the clinical research and the latest patents for using epigenetic drugs to reverse EGFR-TKIs resistance in human cancer. In the future, more novel targets may be discovered for overcoming resistance to EGFR-TKIs, not just on histone deacetylases (HDACs). The dosing course and mode of administration of the combination therapy containing epigenetic drugs need further study. This review provides new ideas for using epigenetic agents to overcome EGFR-TKIs resistance.

Cellular and molecular functions of SETD2 in the central nervous system.

The covalent modification of histones is critical for many biological functions in mammals, including gene regulation and chromatin structure. Posttranslational histone modifications are added and removed by specialised 'writer' and 'eraser' enzymes, respectively. One such writer protein implicated in a wide range of cellular processes is SET domain-containing 2 (SETD2), a histone methyltransferase that catalyses the trimethylation of lysine 36 on histone H3 (H3K36me3). Recently, SETD2 has also been found to modify proteins other than histones, including actin and tubulin. The emerging roles of SETD2 in the development and function of the mammalian central nervous system (CNS) are of particular interest as several SETD2 variants have been implicated in neurodevelopmental disorders, such as autism spectrum disorder and the overgrowth disorder Luscan-Lumish syndrome. Here, we summarise the numerous roles of SETD2 in mammalian cellular functions and development, with a focus on the CNS. We also provide an overview of the consequences of SETD2 variants in human disease and discuss future directions for understanding essential cellular functions of SETD2.

Epigenetic Biomarkers of Metabolic Responses to Lifestyle Interventions.

Studies have examined the possible utility of epigenetic phenomena (DNA methylation changes, covalent histone modifications, and miRNA expression patterns) in predicting individual responses to different lifestyle programs. Nonetheless, most available evidence is focused on identifying epigenetic marks eventually associated with body composition and adiposity outcomes, whereas their roles in metabolic endings remain less explored. This document comprehensively reviewed the evidence regarding the use of epigenetic signatures as putative biomarkers of metabolic outcomes (glycemic, lipid, blood pressure, and inflammatory/oxidative stress features) in response to different lifestyle interventions in humans. Although more investigation is still necessary in order to translate this knowledge in clinical practice, these scientific insights are contributing to the design of advanced strategies for the precise management of cardiometabolic risk, gaining understanding on metabolic heterogeneity, allowing for the prediction of metabolic outcomes, and facilitating the design of epigenome-based nutritional strategies for a more customized approach for metabolic alterations treatment under the scope of precision nutrition.

Polycomb proteins translate histone methylation to chromatin folding

Epigenetic repression often involves covalent histone modifications. Yet, how the presence of a histone mark translates into changes in chromatin structure that ultimately benefits the repression is largely unclear. Polycomb group proteins comprise a family of evolutionarily conserved epigenetic repressors. They act as multi-subunit complexes one of which tri-methylates histone H3 at Lysine 27 (H3K27). Here we describe a novel Monte Carlo-Molecular Dynamics simulation framework, which we employed to discover that stochastic interaction of Polycomb Repressive Complex 1 (PRC1) with tri-methylated H3K27 is sufficient to fold the methylated chromatin. Unexpectedly, such chromatin folding leads to spatial clustering of the DNA elements bound by PRC1. Our results provide further insight into mechanisms of epigenetic repression and the process of chromatin folding in response to histone methylation.

Recognition of H2AK119ub plays an important role in RSF1-regulated early Xenopus development.

Polycomb group (PcG) proteins are key regulators of gene expression and developmental programs via covalent modification of histones, but the factors that interpret histone modification marks to regulate embryogenesis are less studied. We previously identified Remodeling and Spacing Factor 1 (RSF1) as a reader of histone H2A lysine 119 ubiquitination (H2AK119ub), the histone mark deposited by Polycomb Repressive Complex 1 (PRC1). In the current study, we used Xenopus laevis as a model to investigate how RSF1 affects early embryonic development and whether recognition of H2AK119ub is important for the function of RSF1. We showed that knockdown of Xenopus RSF1, rsf1, not only induced gastrulation defects as reported previously, but specific targeted knockdown in prospective neural precursors induced neural and neural crest defects, with reductions of marker genes. In addition, similar to knockdown of PRC1 components in Xenopus, the anterior-posterior neural patterning was affected in rsf1 knockdown embryos. Binding of H2AK119ub appeared to be crucial for rsf1 function, as a construct with deletion of the UAB domain, which is required for RSF1 to recognize the H2AK119ub nucleosomes, failed to rescue rsf1 morphant embryos and was less effective in interfering with early Xenopus development when ectopically expressed. Furthermore, ectopic deposition of H2AK119ub on the Smad2 target gene gsc using a ring1a-smad2 fusion protein led to ectopic recruitment of RSF1. The fusion protein was inefficient in inducing mesodermal markers in the animal region or a secondary axis when expressed in the ventral tissues. Taken together, our results reveal that rsf1 modulates similar developmental processes in early Xenopus embryos as components of PRC1 do, and that RSF1 acts at least partially through binding to the H2AK119ub mark via the UAB domain during development.

An Efficient Protocol for CUT&RUN Analysis of FACS-Isolated Mouse Satellite Cells.

Genome-wide analyses with small cell populations are a major constraint for studies, particularly in the stem cell field. This work describes an efficient protocol for the fluorescence-activated cell sorting (FACS) isolation of satellite cells from the limb muscle, a tissue with a high content of structural proteins. Dissected limb muscles from adult mice were mechanically disrupted by mincing in medium supplemented with dispase and type I collagenase. Upon digestion,the homogenate was filtered through cell strainers, and cells were suspended in FACS buffer. Viability was determined with fixable viability stain, and immunostained satellite cells were isolated by FACS. Cells were lysed with Triton X-100 and released nuclei were bound to concanavalin A magnetic beads. Nucleus/bead complexes were incubated with antibodies against the transcription factor or histone modifications of interest. After washes, nucleus/bead complexes were incubated with protein A-micrococcal nuclease, and chromatin cleavage was initiated with CaCl2. After DNA extraction, libraries were generated and sequenced, and the profiles for genome-wide transcription factor binding and covalent histone modifications were obtained by bioinformatic analysis. The peaks obtained for the various histone marks showed that the binding events were specific for satellite cells. Moreover, known motif analysis unveiled that the transcription factor was bound to chromatin via its cognate response element. This protocol is therefore adapted to study gene regulation in adult mice limb muscle satellite cells.

Comprehensive analysis of the coding and non-coding RNA transcriptome expression profiles of hippocampus tissue in tx-J animal model of Wilson's disease

Wilson's disease (WD) is an autosomal recessive disorder with a genetic basis. The predominant non-motor symptom of WD is cognitive dysfunction, although the specific genetic regulatory mechanism remains unclear. Tx-J mice, with an 82% sequence homology of the ATP7B gene to the human gene, are considered the most suitable model for WD. This study employs deep sequencing to investigate the differences in RNA transcript profiles, both coding and non-coding, as well as the functional characteristics of the regulatory network involved in WD cognitive impairment. The cognitive function of tx-J mice was evaluated using the Water Maze Test (WMT). Long non-coding RNA (lncRNA), circular RNA (circRNA), and messenger RNA (mRNA) profiles were analyzed in the hippocampal tissue of tx-J mice to identify differentially expressed RNAs (DE-RNAs). Subsequently, the DE-RNAs were used to construct protein–protein interaction (PPI) networks, as well as DE-circRNAs and lncRNAs-associated competing endogenous RNA (ceRNA) expression networks, and coding-noncoding co-expression (CNC) networks. To elucidate their biological functions and pathways, the PPI and ceRNA networks were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A total of 361 differentially expressed mRNAs (DE-mRNAs), comprising 193 up-regulated and 168 down-regulated mRNAs, 2627 differentially expressed long non-coding RNAs (DE-lncRNAs), consisting of 1270 up-regulated and 1357 down-regulated lncRNAs, and 99 differentially expressed circular RNAs (DE-circRNAs), consisting of 68 up-regulated and 31 down-regulated circRNAs, were observed in the tx-J mice group when compared to the control mice group. Gene Ontology (GO) and pathway analyses revealed that DE-mRNAs were enriched in cellular processes, calcium signaling pathways, and mRNA surveillance pathways. In contrast, the DE-circRNAs-associated competing endogenous RNA (ceRNA) network was enriched for covalent chromatin modification, histone modification, and axon guidance, whereas the DE-lncRNAs-associated ceRNA network was enriched for dendritic spine, regulation of cell morphogenesis involved in differentiation, and mRNA surveillance pathway. The study presented the expression profiles of lncRNA, circRNA, and mRNA in the hippocampal tissue of tx-J mice. Furthermore, the study constructed PPI, ceRNA, and CNC expression networks. The findings are significant in comprehending the function of regulatory genes in WD associated with cognitive impairment. These results also offer valuable information for the diagnosis and treatment of WD.

Modeling of covalent modifications of histones to estimate the binding affinity.

Covalent histone modifications such as methylation, acetylation, phosphorylation, and other epigenetic modifications of the chromatin play an essential role in regulating eukaryotic cells of which most of these reactions are catalyzed by the enzymes. The binding energy of enzymes is often determined by experimental data via mathematical and statistical models due to specific modifications. Many theoretical models have been introduced to study histone modifications and reprogramming experiments in mammalian cells, in which all efforts in determining the affinity binding are essential part of the work. Here, we introduce a one-dimensional statistical Potts model to accurately determine the enzyme's binding free energy using the experimental data for various types of cells. We study the methylation of lysine 4 and 27 on histone H3 and suppose that each histone has one modification site with one of the seven states: H3K27me3, H3K27me2, H3K27me1, unmodified, H3K4me1, H3K4me2, and H3K4me3. Based on this model, the histone covalent modification is described. Moreover, by using simulation data, the histone's binding free energy and the energy of chromatin states are determined, when they are subject to changes from unmodified to active or repressive states, by finding the probability of the transition.

Histone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.

Treatment of HeLa cells with the DNA damaging agent, bleomycin (BLM), results in the formation of a nonenzymatic 5-methylene-2-pyrrolone histone covalent modification on lysine residues (KMP). KMP is much more electrophilic than other N-acyllysine covalent modifications and post-translational modifications, including N-acetyllysine (KAc). Using histone peptides containing KMP, we show that this modification inhibits the class I histone deacetylase, HDAC1, by reacting with a conserved cysteine (C261) located near the active site. HDAC1 is inhibited by histone peptides whose corresponding N-acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, competes with covalent modification by the KMP-containing peptides. HDAC1 is also covalently modified by a KMP-containing peptide in a complex milieu. These data indicate that peptides containing KMP are recognized by HDAC1 and are bound in the active site. The effects on HDAC1 indicate that KMP formation in cells may contribute to the biological effects of DNA damaging agents, such as BLM, that form this nonenzymatic covalent modification.

Epigenetic influences and brain development

In recent years, the amount of scientific data on the involvement of epigenetic processes in the regulation of brain development in postnatal ontogenesis has been rapidly growing. The article provides an overview of scientific research on the mechanisms of epigenetic influences on brain development. Information was searched in the Scopus, Web of Science, MedLine, The Cochrane Library, PubMed, Pedro, Scholar, eLibrary, CyberLeninka and RSCI databases for the period 1940-2022 by keywords: brain development, epigenetics, neuroontogenesis, methylation, histone modifications, chromatin remodeling, non-coding RNAs. Today, the mechanisms of epigenetic influence on the genome include DNA and RNA methylation, covalent modification of histones, chromatin remodeling, and the influence of non-coding RNAs. Epigenetic modifications are often reversible and provide the necessary plasticity for the response of progenitor cells to environmental signals. The influence of each of these factors on the neurodevelopment is considered. The possibility of transsynaptic transmission of hereditary material by means of circular RNA is indicated. The main ways of microRNA influence on brain development are presented and their universality as an «overgenic» regulator of organism adaptation to external conditions is indicated. Data on the relationship of long non-coding RNAs with the regulation of the functional activity of oligodendroglia are presented. Also, the data presented indicate the paths to the pathogenetically determined prevention of congenital brain pathology.

Beyond transcription factors: more regulatory layers affecting soybean gene expression under abiotic stress.

Abiotic stresses such as nutritional imbalance, salt, light intensity, and high and low temperatures negatively affect plant growth and development. Through the course of evolution, plants developed multiple mechanisms to cope with environmental variations, such as physiological, morphological, and molecular adaptations. Epigenetic regulation, transcription factor activity, and post-transcriptional regulation operated by RNA molecules are mechanisms associated with gene expression regulation under stress. Epigenetic regulation, including histone and DNA covalent modifications, triggers chromatin remodeling and changes the accessibility of transcription machinery leading to alterations in gene activity and plant homeostasis responses. Soybean is a legume widely produced and whose productivity is deeply affected by abiotic stresses. Many studies explored how soybean faces stress to identify key elements and improve productivity through breeding and genetic engineering. This review summarizes recent progress in soybean gene expression regulation through epigenetic modifications and circRNAs pathways, and points out the knowledge gaps that are important to study by the scientific community. It focuses on epigenetic factors participating in soybean abiotic stress responses, and chromatin modifications in response to stressful environments and draws attention to the regulatory potential of circular RNA in post-transcriptional processing.

Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors.

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from bone marrow and play critical immunosuppressive functions in autoimmune diseases. Accumulating evidence indicates that the pathophysiology of autoimmune diseases was closely related to genetic mutations and epigenetic modifications, with the latter more common. Epigenetic modifications, which involve DNA methylation, covalent histone modification, and non-coding RNA-mediated regulation, refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. Recently, numerous reports have shown that epigenetic modifications in MDSCs play important roles in the differentiation and development of MDSCs and their suppressive functions. The molecular mechanisms of differentiation and development of MDSCs and their regulatory roles in the initiation and progression of autoimmune diseases have been extensively studied, but the exact function of MDSCs remains controversial. Therefore, the biological and epigenetic regulation of MDSCs in autoimmune diseases still needs to be further characterized. This review provides a detailed summary of the current research on the regulatory roles of DNA methylation, histone modifications, and non-coding RNAs in the development and immunosuppressive activity of MDSCs, and further summarizes the distinct role of MDSCs in the pathogenesis of autoimmune diseases, in order to provide help for the diagnosis and treatment of diseases from the perspective of epigenetic regulation of MDSCs.

Photo-Cross-Linking To Delineate Epigenetic Interactome.

Covalent modifications of DNA and histones are key cellular epigenetic marks to regulate gene functions. Most of these epigenetic marks are added or removed by corresponding enzymes known as writers and erasers, whose catalytic activities normally rely on the presence of cellular metabolites as cofactors. Epigenetic marks can either directly alter the chromatin structure and dynamics through changing the intra-/internucleosomal histone-histone and histone-DNA interactions or recruit readers that further bring in other proteins with chromatin-modifying/remodeling activities to reshape the local and regional chromatin organization. In these two ways, epigenetic modifications modulate diverse DNA-templated processes, such as gene transcription, DNA replication, and DNA damage repair. Therefore, elucidation of the regulatory mechanisms and biological significance of epigenetic marks requires the identification and characterization of the protein-protein, protein-nucleic acid, and protein-small molecule interactions that control the underlying epigenetic processes. Here, we review the recent advances in using photo-cross-linking strategies to interrogate the epigenetic interactome, focusing on the protein-protein interactions mediated by epigenetic marks in histone tails. We also discuss future directions of developing photo-cross-linking-based tools and methods toward the investigation of the binding events in nucleosomal/chromatinic contexts, and toward the in situ capture of the epigenetic interactome in live cells or even organisms.