histone modification chromatin

Chromatin undergoes dynamic regulation through reversible histone post-translational modifications (PTMs), orchestrated by "writers," "erasers," and "readers" enzymes. Dysregulation of these histone modulators is well implicated in shaping the cancer epigenome and providing avenues for precision therapies. The approval of six drugs for cancer therapy targeting histone modulators, along with the ongoing clinical trials of numerous candidates, represents a significant advancement in the field of precision medicine...

H3.3 is a highly conserved nonreplicative histone variant. H3.3 is enriched in promoters and enhancers of active genes, but it is also found within suppressed heterochromatin, mostly around telomeres. Accordingly, H3.3 is associated with seemingly contradicting functions: It is involved in development, differentiation, reprogramming, and cell fate, as well as in heterochromatin formation and maintenance, and the silencing of developmental genes. The emerging view is that different cellular contexts and histone modifications can promote opposing functions for H3...

The development and function of the immune system are controlled by temporospatial gene expression programs, which are regulated by cis-regulatory elements, chromatin structure, and trans-acting factors. In this study, we cataloged the dynamic histone modifications and chromatin interactions at regulatory regions during T helper (Th) cell differentiation. Our data revealed that the H3K4me1 landscape established by MLL4 in naive CD4+ T cells is critical for restructuring the regulatory interaction network and orchestrating gene expression during the early phase of Th differentiation...

Roots are essential to terrestrial plants, as their growth and morphology are crucial for plant development. The growth of the roots is affected and regulated by several internal and external environmental signals and metabolic pathways. Among them, chromatin modification plays an important regulatory role. In this study, we explore the potential roles of the histone deacetylase AtHD2D in root development and lay the foundation for further research on the biological processes and molecular mechanisms of AtHD2D in the future...

The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8-dependent neurodevelopmental disorders. Using loss- and gain-of-function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes...

PURPOSE OF REVIEW: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure. RECENT FINDINGS: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed...

Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2...

Transposable elements and other repeats are repressed by small-RNA-guided histone modifications in fungi, plants and animals. The specificity of silencing is achieved through base-pairing of small RNAs corresponding to the these genomic loci to nascent noncoding RNAs, which allows the recruitment of histone methyltransferases that methylate histone H3 on lysine 9. Self-reinforcing feedback loops enhance small RNA production and ensure robust and heritable repression. In the unicellular ciliate Paramecium tetraurelia, small-RNA-guided histone modifications lead to the elimination of transposable elements and their remnants, a definitive form of repression...

Crop production is increasingly threatened by the escalating weather events and rising temperatures associated with global climate change. Plants have evolved adaptive mechanisms, including stress memory, to cope with abiotic stresses such as heat, drought, and salinity. Stress memory involves priming, where plants remember prior stress exposures, providing enhanced responses to subsequent stress events. Stress memory can manifest as somatic, intergenerational, or transgenerational memory, persisting for different durations...

Chromatin regulators are indispensable upstream epigenetic regulators.The emergence and progression of atherosclerosis has been demonstrated to be influenced by smooth muscle-related chromatin regulators, such as ZEB2 and MAFF. However, specific chromatin regulators and their possible roles have not been clarified. Information was gathered from 51 patients diagnosed with coronary artery disease (CAD) and 50 individuals in good health from the GEO database. 440 genes were identified as having differential expression across the two datasets, and these genes were linked to cellular reactions...

DNA methylation and posttranslational modifications of histones instruct gene expression in eukaryotes. Besides canonical histones, histone variants also play a critical role in transcriptional regulation. One of the best studied histone variants in plants is H2A.Z whose removal from gene bodies correlates with increased transcriptional activity. The eviction of H2A.Z is regulated by environmental cues such as increased ambient temperatures, and current models suggest that H2A.Z functions as a transcriptional buffer preventing environmentally responsive genes from undesired activation...

Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. However, a broader hypothesis suggests that chromatin compaction can be both a cause and a consequence of the locus histone modification state, with a tight bidirectional interaction underpinning bistable transcriptional states. To rigorously test this hypothesis, we developed a mathematical model for the dynamics of the HMR locus in Saccharomyces cerevisiae , that incorporates activating histone modifications, silencing proteins, and a dynamic, acetylation-dependent, three-dimensional locus size...

Mycobacterium tuberculosis (Mtb) employs several sophisticated strategies to evade host immunity and facilitate its intracellular survival. One of them is the epigenetic manipulation of host chromatin by three strategies i.e., DNA methylation, histone modifications and miRNA involvement. A host-directed therapeutic can be an attractive approach that targets these host epigenetics or gene regulations and circumvent manipulation of host cell machinery by Mtb. Given the complexity of the nature of intracellular infection by Mtb, there are challenges in identifying the important host proteins, non-coding RNA or the secretory proteins of Mtb itself that directly or indirectly bring upon the epigenetic modifications in the host chromatin...

Long-term perturbation of de novo chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of Chromatin Assembly Factor 1 (CAF-1), a key player in de novo chromatin assembly, with single-cell genomics, quantitative proteomics, and live-microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyper-accessible...

The epigenome can adequately regulate the on/off states of genes in response to external environmental factors and stress. In recent years, it has been observed that the epigenome, which is modulated through DNA methylation, histone modifications, and chromatin remodeling, changes with age. Alterations in the epigenome lead to the loss of cell-specific epigenome/identity, which in turn triggers a decline in tissue function. In mammals, postnatal epigenomic variations are not only caused by metabolic diseases, such as diabetes or DNA damage, but also by social stress and infectious diseases...

BACKGROUND: Histone modifications play a critical role in chromatin remodelling and regulate gene expression in health and disease. Histone methyltransferases EZH1, EZH2, and demethylases UTX, JMJD3, and UTY catalyse trimethylation of lysine 27 on histone H3 (H3K27me3). This study was designed to investigate whether H3K27me3 triggers hyperglycemia-induced oxidative and inflammatory transcriptional programs in the endothelium. METHODS: We studied human aortic endothelial cells exposed to high glucose (HAEC) or isolated from individuals with diabetes (D-HAEC)...

Developmental phenotypic changes can evolve under selection imposed by age- and size-related ecological differences. Many of these changes occur through programmed alterations to gene expression patterns, but the molecular mechanisms and gene-regulatory networks underlying these adaptive changes remain poorly understood. Many venomous snakes, including the eastern diamondback rattlesnake ( Crotalus adamanteus ), undergo correlated changes in diet and venom expression as snakes grow larger with age, providing models for identifying mechanisms of timed expression changes that underlie adaptive life history traits...

Cell fate conversion is associated with extensive post-translational modifications (PTMs) and architectural changes of sub-organelles, yet how these events are interconnected remains unknown. We report here the identification of a phosphorylation code in 14-3-3 binding motifs (PC14-3-3) that greatly stimulates induced cardiomyocyte (iCM) formation from fibroblasts. PC14-3-3 is identified in pivotal functional proteins for iCM reprogramming, including transcription factors and chromatin modifiers. Akt1 kinase and protein phosphatase 2A are the key writer and key eraser of the PC14-3-3 code, respectively...

Epigenetic modification shapes differentiation trajectory and regulates the exhaustion state of chimeric antigen receptor T (CAR-T) cells. Limited efficacy induced by terminal exhaustion closely ties with intrinsic transcriptional regulation. However, the comprehensive regulatory mechanisms remain largely elusive. Here, we identify class I histone deacetylase inhibitors (HDACi) as boosters of CAR-T cell function by high-throughput screening of chromatin-modifying drugs, in which M344 and chidamide enhance memory maintenance and resistance to exhaustion of CAR-T cells that induce sustained antitumor efficacy both in vitro and in vivo...

Histone methylation plays crucial roles in regulating chromatin structure and gene transcription in epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases. LSD1 dysregulation is closely associated with cancer, viral infections, and neurodegenerative diseases, etc., making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage...