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Results for “Histone Modifications”

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At least 127 records · Page 7Linked to original sources
PubMed2002

SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities.

Histone deacetylation plays a central role in the regulation of genes linked to virtually all biological processes. This modification reaction is dependent on a family of related histone deacetylases (HDACs), which function as key components of large multiprotein complexes involved in the development of normal and neoplastic cells. The mechanisms regulating HDACs and their roles in such processes are not understood, and these form the major focus for the current study. Here, in the course of assessing possible post-translational modifications of HDAC1, we demonstrated that HDAC1 is a substrate for SUMO-1 (small ubiquitin-related modifier) modification in vitro and in vivo. The HDAC1 lysines targeted for modification were identified as C-terminal Lys-444 and Lys-476, which are also present in mammalian HDAC2 and lower vertebrate HDAC1/2 orthologs yet absent from other HDAC family members, pointing to a means of differential regulation among HDAC proteins. Mutation of these target residues (lysine to arginine substitution) profoundly reduced HDAC1-mediated transcriptional repression in reporter assays without affecting HDAC1 ability to associate with mSin3A and eliminated HDAC1-induced cell cycle and apoptotic responses upon overexpression. Together, the results demonstrate that HDAC1 is modified by SUMO-1, and this modification can dramatically affect HDAC1 activity in a number of surrogate biological assays.

3T3 Cells↗
PubMed2025

RNA Pol I activity is required for meiotic chromatin organization and the H3K4me3 gradient essential for oogenesis, independent of ribosome synthesis.

Oogenesis requires extensive and dynamic chromatin remodeling that primes gene promoters for later transcriptional activation during embryonic development. Here, we uncover a pivotal, non-canonical role for RNA Polymerase I (Pol I) in driving these chromatin state transitions during Caenorhabditis elegans oogenesis. Using the auxin-inducible degron system to selectively deplete either Pol I catalytic subunits or ribosome assembly factors, we disentangle the consequences of impaired nucleolar integrity from reductions in ribosome biogenesis. Strikingly, although disrupting ribosome assembly caused minimal effects on oocyte production, loss of Pol I activity led to widespread changes in chromatin accessibility, a dampening of the distal-proximal H3K4me3 gradient required for oogenesis, reduced synapsis, and elevated ATM/ATR phosphorylation, resulting in fewer but significantly larger oocytes. Despite their promoters becoming more accessible, oogenesis genes did not show large changes in steady-state mRNA, consistent with transcriptional repression prior to fertilization. Instead, Pol I depletion prematurely remodeled oogenic chromatin, through a misdirection of H3K4me3 deposition towards promoters normally primed for zygotic genome activation. These findings reveal an epigenetic gating function for nucleolar integrity in oocyte maturation: Pol I preserves three-dimensional chromatin organization and maintains proper spatiotemporal regulation of histone modifications, independent of ribosome production. Given the evolutionary conservation of nucleolar dynamics and histone modifications during gametogenesis, our work suggests that nucleolar stress, whether from environmental factors, aging, or genetic disorders, could broadly compromise fertility by disrupting oogenic chromatin priming.

Journal Article↗
PubMed1984

Histone H3 modification in BHK cells infected with foot-and-mouth disease virus.

Infection of BHK cells with foot-and-mouth disease virus (FMDV) causes a thorough change in the electrophoretic profile of whole nuclear histones. It consists in the disappearance of histone H3 and the appearance of a new polypeptide (Pi) which migrates between histones H2A and H4 on SDS-polyacrylamide gels. Protein Pi is detected at 2 hr postinfection (pi), the time in which viral RNA synthesis begins to increase, and reaches equimolecular amounts with the remaining core histones 1 hr later, when the disappearance of histone H3 is almost complete. Labeling of cells prior to infection demonstrates that Pi is not a novo product but the result of a viral-induced processing of a host precursor synthetized beforehand. Protein Pi comigrates with histone H2A/B in acetic acid/urea polyacrylamide gels and it shares common major peptides with histone H3 under controlled proteolysis with protease V8 or trypsin. The mononucleosomal and nucleosomal DNA pattern analysis after micrococcal nuclease treatment of nuclei from infected and mock-infected cells did not show any significant differences even though after 3 hr (p.i.), protein Pi replaces histone H3 in the nucleosomal structure. It was concluded that FMDV infection is responsible for a specific modification in the nucleus of infected cells which leads, after 3 hr (p.i.), to a complete histone H3 protein Pi transition in the nucleosomes.

Animals↗
PubMed2003

Tissue-specific nuclear architecture and gene expression regulated by SATB1.

Eukaryotic chromosomes are packaged in nuclei by many orders of folding. Little is known about how higher-order chromatin packaging might affect gene expression. SATB1 is a cell-type specific nuclear protein that recruits chromatin-remodeling factors and regulates numerous genes during thymocyte differentiation. Here we show that in thymocyte nuclei, SATB1 has a cage-like 'network' distribution circumscribing heterochromatin and selectively tethers specialized DNA sequences onto its network. This was shown by fluorescence in situ hybridization on wild-type and Satb1-null thymocytes using in vivo SATB1-bound sequences as probes. Many gene loci, including that of Myc and a brain-specific gene, are anchored by the SATB1 network at specific genomic sites, and this phenomenon is precisely correlated with proper regulation of distant genes. Histone-modification analyses across a gene-enriched genomic region of 70 kb showed that acetylation of histone H3 at Lys9 and Lys14 peaks at the SATB1-binding site and extends over a region of roughly 10 kb covering genes regulated by SATB1. By contrast, in Satb1-null thymocytes, this site is marked by methylation at H3 Lys9. We propose SATB1 as a new type of gene regulator with a novel nuclear architecture, providing sites for tissue-specific organization of DNA sequences and regulating region-specific histone modification.

Animals↗
PubMed2001

CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter.

We present here an in vivo view of major histocompatibility complex (MHC) class II promoter assembly, nucleosome modifications and gene expression mediated by the class II transactivator (CIITA). Acetylation and deacetylation of histones H3 and H4 at the HLA-DRA promoter were found to occur during a time-course that depended on CIITA expression and binding. Expression of a CIITA mutant, which lacked the activation domain, induced H4 but not H3 histone acetylation. This suggested that multiple histone acetyltransferase activities are associated with MHC class II expression. H4 acetylation was mapped to Lys8, which implicated several histone acetyltransferases as possible modulators of this activity.

Acetylation↗
PubMed1999

A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity.

Nucleosomal histone modification is believed to be a critical step in the activation of RNA polymerase II-dependent transcription. p300/CBP and PCAF histone acetyltransferases (HATs) are coactivators for several transcription factors, including nuclear hormone receptors, p53, and Stat1alpha, and participate in transcription by forming an activation complex and by promoting histone acetylation. The adenoviral E1A oncoprotein represses transcriptional signaling by binding to p300/CBP and displacing PCAF and p/CIP proteins from the complex. Here, we show that E1A directly represses the HAT activity of both p300/CBP and PCAF in vitro and p300-dependent transcription in vivo. Additionally, E1A inhibits nucleosomal histone modifications by the PCAF complex and blocks p53 acetylation. These results demonstrate the modulation of HAT activity as a novel mechanism of transcriptional regulation.

Acetyltransferases↗
PubMed2026

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Aging↗
PubMed2025

H3K4me2 distinguishes a distinct class of enhancers during the maternal-to-zygotic transition.

After egg fertilization, an initially silent embryonic genome is transcriptionally activated during the maternal-to-zygotic transition. In zebrafish, maternal vertebrate pluripotency factors Nanog, Pou5f3 (OCT4 homolog), and Sox19b (SOX2 homolog) (NPS) play essential roles in orchestrating embryonic genome activation, acting as "pioneers" that open condensed chromatin and mediate acquisition of activating histone modifications. However, some embryonic gene transcription still occurs in the absence of these factors, suggesting the existence of other mechanisms regulating genome activation. To identify chromatin signatures of these unknown pathways, we profiled the histone modification landscape of zebrafish embryos using CUT&RUN. Our regulatory map revealed two subclasses of enhancers distinguished by presence or absence of H3K4me2. Enhancers lacking H3K4me2 tend to require NPS factors for de novo activation, while enhancers bearing H3K4me2 are epigenetically bookmarked by DNA hypomethylation to recapitulate gamete activity in the embryo, independent of NPS pioneering. Thus, parallel enhancer activation pathways combine to induce transcriptional reprogramming to pluripotency in the early embryo.

Animals↗
PubMed2003

Histones are first hyperacetylated and then lose contact with the activated PHO5 promoter.

We have analyzed the histone modification status of the PHO5 promoter from yeast by the ChIP technology and have focused on changes occurring upon activation. Using various acetylation-specific antibodies, we found a dramatic loss of the acetylation signal upon induction of the promoter. This turned out to be due, however, to the progressive loss of histones altogether. The fully remodeled promoter appears to be devoid of histones as judged by ChIP analyses. Local histone hyperacetylation does indeed occur, however, prior to remodeling. This can explain the delay in chromatin remodeling in the absence of histone acetyltransferase activity of the SAGA complex that was previously documented for the PHO5 promoter. Our findings shed new light on the nucleosomal structure of fully remodeled chromatin. At the same time, they point out the need for novel controls when the ChIP technique is used to study histone modifications in the context of chromatin remodeling in vivo.

Acetylation↗
PubMed2003

Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome.

To clarify the chromatin-based imprinting mechanism of the p57(KIP2)/LIT1 subdomain at chromosome 11p15.5 and the mouse ortholog at chromosome 7F5, we investigated the histone-modification status at a differentially CpG methylated region of Lit1/LIT1 (DMR-Lit1/LIT1), which is an imprinting control region for the subdomain and is demethylated in half of patients with Beckwith-Wiedemann syndrome (BWS). Chromatin-immunoprecipitation assays revealed that, in both species, DMR-Lit1/LIT1 with the CpG-methylated, maternally derived inactive allele showed histone H3 Lys9 methylation, whereas the CpG-unmethylated, paternally active allele was acetylated on histone H3/H4 and methylated on H3 Lys4. We have also investigated the relationship between CpG methylation and histone H3 Lys9 methylation at DMR-LIT1 in patients with BWS. In a normal individual and in patients with BWS with normal DMR-LIT1 methylation, histone H3 Lys9 methylation was detected on the maternal allele; however, it disappeared completely in the patients with the DMR-LIT1 imprinting defect. These findings suggest that the histone-modification status at DMR-Lit1/LIT1 plays an important role in imprinting control within the subdomain and that loss of histone H3 Lys9 methylation, together with CpG demethylation on the maternal allele, may lead to the BWS phenotype.

Base Sequence↗
PubMed2003

Two means of transcriptional reactivation within heterochromatin.

DNA methylation levels and specific histone modifications of chromatin in interphase nuclei are taken as an indicator of transcriptional activity or silencing. Arabidopsis mutants impaired in maintenance of transcriptional gene silencing (TGS) alleviate TGS with or without affecting DNA methylation. Mutant ddm1, representing the first type, lacks a chromatin remodeling factor that regulates histone and DNA methylation. Mutant mom1, representing the second type, is affected in a different but still unknown silencing mechanism. Both classes of mutation have been studied mainly for their effects on specific loci. Here, we describe the cytological analysis of chromatin in ddm1 and mom1 mutants. The ddm1 mutation causes a striking decondensation of centromeric heterochromatin, a re-distribution of the remaining methylation of DNA, and a drastic change in the pattern of histone modification. A complex transgenic locus, which underwent stable inactivation and became heterochromatin-like, follows similar structural alterations. In contrast, nuclear organization in mom1 appears unaltered, demonstrating an involvement of MOM1 in transcriptional regulation within a heterochromatic environment.

Arabidopsis↗
PubMed2003

A novel lipid hydroperoxide-derived cyclic covalent modification to histone H4.

Previous studies have established that 4-hydroxy-2-nonenal is a lipid hydroperoxide-derived aldehydic bifunctional electrophile that reacts with DNA and proteins. However, it has now been recognized that 4-oxo-2-nonenal is also a major product of lipid hydroperoxide decomposition. Furthermore, 4-oxo-2-nonenal is more reactive than 4-hydroxy-2-nonenal toward the DNA-bases 2'-deoxyguanosine, 2'-deoxyadenosine, and 2'-deoxycytidine and proteins. The formation of 4-oxo-2-nonenal can be induced through vitamin C-mediated or transition metal ion-mediated homolytic decomposition of polyunsaturated omega-3 lipid hydroperoxides such as 13(S)-hydroperoxyoctadecadienoic acid. We have discovered that synthetic 4-oxo-nonenal or 4-oxo-2-nonenal-generated from 13(S)-hydroperoxyoctadecadienoic acid recognizes the specific amino acid motifs of His75, Ala76, and Lys77 in bovine histone H4. Reaction of the histidine and lysine residues with 4-oxo-2-nonenal results in the formation of a novel cyclic structure within the protein. The cyclic structure incorporates the histidine imidazole ring and a newly formed pyrrole derived from the lysine. The cyclic imidazole-pyrrole derivative that is formed from the small Nalpha-acetyl-His-Ala-Lys peptide exists as a mixture of two atropisomers that inter-convert upon heating. Such lipid hydroperoxide-derived modifications could potentially modulate transcriptional activation in vivo. Furthermore, the ability to synthesize cyclic peptides using 4-oxo-2-nonenal will facilitate the preparation of novel structural analogs with potential biological activity.

Aldehydes↗
PubMed2026

Beyond Bulk: Cell-Type-Resolved Epigenomics as the Path Forward in Alzheimer's Disease Research.

Alzheimer's disease (AD) is a complex neurodegenerative disorder in which most risk variants are noncoding and are enriched at gene regulatory regions, implicating epigenetic mechanisms as central mediators of disease pathogenesis. For most of the history of AD epigenetics research, bulk tissue analysis has dominated, obscuring the fundamentally distinct epigenomic landscapes of individual brain cell types and masking cell-type-specific contributions to disease. Advances in single-cell and single-nucleus sequencing, fluorescence-activated nuclei sorting and multiplexed epigenomic platforms have transformed this landscape, enabling cell-type-resolved profiling of chromatin accessibility, DNA methylation, histone modifications and transcription across the major neuronal, glial and neurovascular populations of the human brain. Here, we review these advances, structured around the argument that cell-type resolution is not a methodological refinement but a conceptual necessity. We describe the distinct epigenomic programs disrupted in neurons, microglia, astrocytes, oligodendrocytes and neurovascular cells in AD, highlighting how each cell type responds to pathology. We discuss the discovery of epigenomic erosion, the progressive loss of cell-type-specific epigenomic identity across virtually all brain cell populations as AD advances, as a unifying disease mechanism linking chromatin dysregulation to cognitive decline. Finally, we identify critical gaps in current knowledge, including the near-complete absence of cell-type-resolved histone modification and DNA methylation data for most brain cell types, the underrepresentation of rare populations in standard preparations and the untapped potential of metabolic acylation marks as indicators of the epigenome-metabolism interface in neurodegeneration.

Humans↗
PubMed2026

LncRNA HOTAIR contributes to cigarette smoke-induced pro-inflammatory responses in human airway epithelial cells.

Inhalation of cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), inducing epigenetic changes in the airway epithelium, including dysregulation of long-noncoding RNAs (lncRNAs). LncRNA homeobox gene transcript antisense RNA (HOTAIR) regulates chromatin remodeling and has been implicated in CS-induced malignant transformation. We hypothesized that HOTAIR expression is altered in COPD, leading to airway epithelial abnormalities. HOTAIR expression and overall survival were studied in The Cancer Genome Atlas (TCGA) database. Airway epithelial cells (AECs) were isolated from transplanted lungs of 11 patients with COPD, tracheobronchial tissue of 9 non-COPD donors, and bronchial brushings of ex-smokers with/without COPD (n = 6/group). HOTAIR expression, histone modifications, and production of proinflammatory cytokines (CXCL8 and GM-CSF) were assessed in the absence/presence of CS extract (CSE) and HOTAIR-polycomb inhibitor AQB. High HOTAIR expression correlated with poor overall survival in cancer patients with COPD, but not those without. Although HOTAIR expression was not significantly different between AECs from controls and subjects with COPD at baseline, it was significantly increased by 20% CSE only in COPD-derived AECs. CSE significantly decreased H3K4me3 levels in COPD-derived AECs, but not those from controls. AQB reduced baseline H3K27me3 levels in both groups, with a stronger effect in control-derived AECs. In addition, it reduced H3K4me3 levels in the presence of CSE in both groups. Finally, although AQB significantly suppressed CSE-induced production of GM-CSF and CXCL8 in control AECs, it failed to do so in COPD. Together, these findings suggest that COPD-derived AECs are more susceptible to CSE-induced HOTAIR upregulation, which may have a proinflammatory effect that cannot be inhibited by AQB.NEW & NOTEWORTHY COPD-derived AECs exhibit higher susceptibility to CSE-induced HOTAIR upregulation. CSE induces distinct histone modification patterns (H3K4me3) specifically in COPD-derived AECs. HOTAIR is essential for mediating CSE-induced proinflammatory responses in AECs.

Humans↗
PubMed2025

CRISPRoff epigenome editing for programmable gene silencing in human cell lines and primary T cells.

The advent of CRISPR-based technologies has enabled the rapid advancement of programmable gene manipulation in cells, tissues, and whole organisms. An emerging platform for targeted gene perturbation is epigenetic editing, the direct editing of chemical modifications on DNA and histones that ultimately results in repression or activation of the targeted gene. In contrast to CRISPR nucleases, epigenetic editors modulate gene expression without inducing DNA breaks or altering the genomic sequence of host cells. Recently, we developed the CRISPRoff epigenetic editing technology that simultaneously establishes DNA methylation and repressive histone modifications at targeted gene promoters. Transient expression of CRISPRoff and the accompanying single guide RNAs in mammalian cells results in transcriptional repression of targeted genes that is memorized heritably by cells through cell division and differentiation. Here, we describe our protocol for the delivery of CRISPRoff through plasmid DNA transfection, as well as the delivery of CRISPRoff mRNA, into transformed human cell lines and primary immune cells. We also provide guidance on evaluating target gene silencing and highlight key considerations when utilizing CRISPRoff for gene perturbations. Our protocols are broadly applicable to other CRISPR-based epigenetic editing technologies, as programmable genome manipulation tools continue to evolve rapidly.

Humans↗