Explore the vast range of titles available.

Histone modification is one of the key elements in epigenetic control and plays important roles in regulation of biological processes and disease development. Currently, records of human histone modifications with various levels of confidence in evidence are scattered in various knowledgebases and databases. In the present study, a curated catalogue of human histone modifications, CHHM, was obtained by manual retrieval, evidence assessment, and integration of modification records from 10 knowledgebases/databases and 3 complementary articles. CHHM contains 6612 nonredundant modification entries covering 31 types of modifications (including 9 types of emerging modifications) and 2 types of histone-DNA crosslinks, that were identified in 11 H1 variants, 21 H2A variants, 21 H2B variants, 9 H3 variants, and 2 H4 variants. For ease of visualization and accessibility, modification entries are presented with aligned protein sequences in an Excel file. Confidence level in evidence is provided for each entry. Acylation modifications contribute to the highest number of modification entries in CHHM. This supports that cellular metabolic status plays a very important role in epigenetic control. CHHM reveals modification hotspot regions and uneven distribution of the modification entries across the histone families. Such uneven distribution may suggest that a particular histone family is more susceptible to certain types of modifications. CHHM not only serves as an important and user-friendly resource for biomedical and clinical researches involving histone modifications and transcriptional regulation, but also provides new insights for basic researches in the mechanism of human histone modifications and epigenetic control.

Histone posttranslational modifications (PTMs) modulate several eukaryotic cellular processes, including transcription, replication, and repair. Vast arrays of modifications have been identified in conventional eukaryotes over the last 20 to 25 years. While initial studies uncovered these primarily on histone tails, multiple modifications were subsequently found on the central globular domains as well. Histones are evolutionarily conserved across eukaryotes, and a large number of their PTMs and the functional relevance of these PTMs are largely conserved. Histone posttranslational modifications (PTMs) modulate several eukaryotic cellular processes, including transcription, replication, and repair. Vast arrays of modifications have been identified in conventional eukaryotes over the last 20 to 25 years. While initial studies uncovered these primarily on histone tails, multiple modifications were subsequently found on the central globular domains as well. Histones are evolutionarily conserved across eukaryotes, and a large number of their PTMs and the functional relevance of these PTMs are largely conserved. Trypanosomatids, however, are early diverging eukaryotes. Although possessing all four canonical histones as well as several variants, their sequences diverge from those of other eukaryotes, particularly in the tails. Consequently, the modifications they carry also vary. Initial analyses almost 15 years ago suggested that trypanosomatids possessed a smaller collection of histone modifications. However, exhaustive high resolution mass spectrometry analyses in the last few years have overturned this belief, and it is now evident that the “histone code” proposed by Allis and coworkers in the early years of this century is as complex in these organisms as in other eukaryotes. Trypanosomatids cause several diseases, and the members of this group of organisms have varied lifestyles, evolving diverse mechanisms to evade the host immune system, some of which have been found to be principally controlled by epigenetic mechanisms. This minireview aims to acquaint the reader with the impact of histone PTMs on trypanosomatid cellular processes, as well as other facets of trypanosomatid epigenetic regulation, including the influence of three-dimensional (3D) genome architecture, and discusses avenues for future investigations.

The mammalian genome is punctuated by CpG islands (CGIs), which differ sharply from the bulk genome by being rich in G + C and the dinucleotide CpG. CGIs often include transcription initiation sites and display ‘active’ histone marks, notably histone H3 lysine 4 methylation. In embryonic stem cells (ESCs) some CGIs adopt a ‘bivalent’ chromatin state bearing simultaneous ‘active’ and ‘inactive’ chromatin marks. To determine whether CGI chromatin is developmentally programmed at specific genes or is imposed by shared features of CGI DNA, we integrated artificial CGI-like DNA sequences into the ESC genome. We found that bivalency is the default chromatin structure for CpG-rich, G + C-rich DNA. A high CpG density alone is not sufficient for this effect, as A + T-rich sequence settings invariably provoke de novo DNA methylation leading to loss of CGI signature chromatin. We conclude that both CpG-richness and G + C-richness are required for induction of signature chromatin structures at CGIs. The building blocks of DNA are four molecules commonly named ‘A’, ‘T’, ‘C’ and ‘G’. The order of these DNA letters in a gene contains the instructions to make specific proteins or other molecules. Other stretches of DNA contain codes that direct the cell's machinery to genes that need to be switched on or switched off. The start of a gene, for example, has a stretch of DNA called a promoter, which is where the molecular machinery that switches on the gene is assembled. A human cell can contain over two and half metres of DNA. To get this length to fit inside the cell, the DNA is wrapped tightly around proteins to form a structure called chromatin. However, this packing can make it difficult to access the right gene at the right time. As such, chromatin is often marked with small chemical tags that earmark which genes should be either activated or inactivated, and/or that cause the DNA to unpack. Most gene promoters contain a sequence of DNA with many Cs and Gs found one after the other, called a CpG island. Researchers have previously shown that the chromatin of CpG islands has two types of chemical markings—one that normally marks active genes, and another that often marks inactive genes. It was suggested that having both kinds of markings allows CpG islands to prime nearby genes, so that they are ready to be quickly switched on or off as the cell develops. However, the features of the DNA sequence in these CpG islands that are important for this process had not been directly tested. Wachter et al. have now inserted an artificial DNA sequence that included a CpG island into mouse stem cells. The chromatin around these CpG islands was readily marked with both activating and inactivating chemical marks. Furthermore, by changing the sequence of the artificial DNA, Wachter et al. revealed that these chemical marks were only added when the DNA sequences contained a lot of Cs followed by Gs. Other artificial sequences with lots of Cs and Gs, but where Gs were rarely found immediately after the Cs, had neither of the two chemical marks on the chromatin. This suggests that nearby genes would be harder to locate and activate as the cell grows and develops. On the other hand, when the DNA contained a lot of As and Ts, the chemical marks were added directly to the DNA (rather than to the chromatin)—and this prevented both the activating and the inactivating chemical marks being added to the chromatin. Now that the common features of CpG islands that influence chromatin are known, the next step is to find out how this is achieved. Further work will be needed to uncover which proteins in a cell interpret these DNA sequence such that nearby genes can be switched on or off.

Aging is the process of gradual physiological deterioration till death and this process perpetually reduce the functionality of an individual. To address the rationale and provide geriatric care, the constant target of geroscience is to identify reliable biomarkers for aging. Over the past decades, diversified advancements in epigenetic studies crescively support the fact that the accumulation of epigenetic changes accompanies the process of aging. A growing number of studies have suggested that alterations occur through three fundamental mechanisms like methylation of DNA, histone protein modification, and production of non‐coding microRNAs. Each of these changes occurs silently and provokes alterations in the circumstantial expression of genetic material without altering the underlying gene sequences. The changes in gene expression due to epigenetic alterations are suggested to be the cause of early aging and the onset of age‐related health risks. This review would attempt to give an integrated overview of epigenetic changes related to aging and age‐associated health risks. This review also discussed epigenomes influencing early aging and factors modulating it. Since epigenetic changes are reversible, early identification of epigenetic markers can be a hope for future geriatric medicine. Finally, this review emphasizes the identification of blood‐based epigenetic biomarkers in order to enlighten the future scope for therapeutic intervention to slow down the aging process. An epigenetic alteration like DNA methylation, Histone modification, or miRNA production can potentially influence an individual's genetic expression without changing their sequence. The change in epigenome‐induced genetic alteration can cause early aging and age‐related health risk. This is an informative mini‐review to summarize the fact behind epigenetics and aging.

Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is unknown. Class I histone deacetylases (including HDAC1, 2, 3, and 8) are one of the major classes of the HDAC family and catalyze the removal of acetyl groups from lysine residues in histones and cellular proteins. Class I HDACs exhibit distinct cellular and subcellular expression patterns and are involved in many biological processes and diseases through diverse signaling pathways. However, the link between class I HDACs and uLMS is still being determined. In this study, we assessed the expression panel of Class I HDACs in uLMS and characterized the role and mechanism of class I HDACs in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that HDAC1, 2, and 3 are aberrantly upregulated in uLMS tissues compared to adjacent myometrium. Immunoblot analysis demonstrated that the expression levels of HDAC 1, 2, and 3 exhibited a graded increase from normal and benign to malignant uterine tumor cells. Furthermore, inhibition of HDACs with Class I HDACs inhibitor (Tucidinostat) decreased the uLMS proliferation in a dose-dependent manner. Notably, gene set enrichment analysis of differentially expressed genes (DEGs) revealed that inhibition of HDACs with Tucidinostat altered several critical pathways. Moreover, multiple epigenetic analyses suggested that Tucidinostat may alter the transcriptome via reprogramming the oncogenic epigenome and inducing the changes in microRNA-target interaction in uLMS cells. In the parallel study, we also determined the effect of DL-sulforaphane on the uLMS. Our study demonstrated the relevance of class I HDACs proteins in the pathogenesis of malignant uLMS. Further understanding the role and mechanism of HDACs in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.

It is difficult to identify histone modification from datasets that contain high-throughput sequencing data. Although multiple methods have been developed to identify histone modification, most of these methods are not specific to histone modification but are general methods that aim to identify protein binding to the genome. In this study, tensor decomposition (TD) and principal component analysis (PCA)-based unsupervised feature extraction with optimized standard deviation were successfully applied to gene expression and DNA methylation. The proposed method was used to identify histone modification. Histone modification along the genome is binned within the region of length L. Considering principal components (PCs) or singular value vectors (SVVs) that PCA or TD attributes to samples, we can select PCs or SVVs attributed to regions. The selected PCs and SVVs further attribute p-values to regions, and adjusted p-values are used to select regions. The proposed method identified various histone modifications successfully and outperformed various state-of-the-art methods. This method is expected to serve as a de facto standard method to identify histone modification. For reproducibility and to ensure the systematic analysis of our study is applicable to datasets from different gene expression experiments, we have made our tools publicly available for download from gitHub.

Preeclampsia (PE) is a severe pregnancy disorder with a pathophysiology not yet completely understood and without curative therapy. The histone modifications H3K4me3 and H3K9ac, as well as galectin-2 (Gal-2), are known to be decreased in PE. To gain a better understanding of the development of PE, the influence of Gal-2 on histone modification in trophoblasts and in syncytialisation was investigated. Immunohistochemical stains of 13 PE and 13 control placentas were correlated, followed by cell culture experiments. An analysis of H3K4me3 and H3K9ac was conducted, as well as cell fusion staining with E-cadherin and β-catenin—both after incubation with Gal-2. The expression of H3K4me3 and H3K9ac correlated significantly with the expression of Gal-2. Furthermore, we detected an increase in H3K4me3 and H3K9ac after the addition of Gal-2 to BeWo/HVT cells. Moreover, there was increased fusion of HVT cells after incubation with Gal-2. Gal-2 is associated with the histone modifications H3K4me3 and H3K9ac in trophoblasts. Furthermore, syncytialisation increased after incubation with Gal-2. Therefore, we postulate that Gal-2 stimulates syncytialisation, possibly mediated by H3K4me3 and H3K9ac. Since Gal-2, as well as H3K4me3 and H3K9ac, are decreased in PE, the induction of Gal-2 might be a promising therapeutic target.

Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ) in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM), which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails. Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI) method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2). Protein level of DNA methyltransferase 3B (DNMT3B) and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant. OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.

Epigenetics is a discipline that studies heritable changes in gene expression that do not involve altering the DNA sequence. Over the past decade, researchers have shown that epigenetic regulation plays a momentous role in cell growth, differentiation, autoimmune diseases, and cancer. The main epigenetic mechanisms include the well-understood phenomenon of DNA methylation, histone modifications, and regulation by non-coding RNAs, a mode of regulation that has only been identified relatively recently and is an area of intensive ongoing investigation. It is generally known that the majority of human transcripts are not translated but a large number of them nonetheless serve vital functions. Non-coding RNAs are a cluster of RNAs that do not encode functional proteins and were originally considered to merely regulate gene expression at the post-transcriptional level. However, taken together, a wide variety of recent studies have suggested that miRNAs, piRNAs, endogenous siRNAs, and long non-coding RNAs are the most common regulatory RNAs, and, significantly, there is a growing body of evidence that regulatory non-coding RNAs play an important role in epigenetic control. Therefore, these non-coding RNAs (ncRNAs) highlight the prominent role of RNA in the regulation of gene expression. Herein, we summarize recent research developments with the purpose of coming to a better understanding of non-coding RNAs and their mechanisms of action in cells, thus gaining a preliminary understanding that non-coding RNAs feed back into an epigenetic regulatory network.

Aging is the progressive decline or loss of function at the cellular, tissue, and organismal levels that ultimately leads to death. A number of external and internal factors, including diet, exercise, metabolic dysfunction, genome instability, and epigenetic imbalance, affect the lifespan of an organism. These aging factors regulate transcriptome changes related to the aging process through chromatin remodeling. Many epigenetic regulators, such as histone modification, histone variants, and ATP-dependent chromatin remodeling factors, play roles in chromatin reorganization. The key to understanding the role of gene regulatory networks in aging lies in characterizing the epigenetic regulators responsible for reorganizing and potentiating particular chromatin structures. This review covers epigenetic studies on aging, discusses the impact of epigenetic modifications on gene expression, and provides future directions in this area.