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At least 19 recordsLinked to original sources
PubMed2025

Histone modifications in the regulation of erythropoiesis.

INTRODUCTION: The pathogenesis of anemia and other erythroid dysphasia are mains poorly understood, primarily due to limited knowledge about the differentiation processes and regulatory mechanisms governing erythropoiesis. Erythropoiesis is a highly complex and precise biological process, that can be categorized into three distinct stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation, and this complex process is tightly controlled by multiple regulatory factors. Emerging evidence highlights the crucial role of epigenetic modifications, particularly histone modifications, in regulating erythropoiesis. Methylation and acetylation are two common modification forms that affect genome accessibility by altering the state of chromatin, thereby regulating gene expression during erythropoiesis. DISCUSSION: This review systematically examines the roles of histone methylation and acetylation, along with their respective regulatory enzymes, in regulating the development and differentiation of hematopoietic stem/progenitor cells (HSPCs) and erythroid progenitors. Furthermore, we discuss the involvement of these histone modifications in erythroid-specific developmental processes, including hemoglobin switching, chromatin condensation, and enucleation.Conclusions This review summarizes the current understanding of the role of histone modifications in erythropoiesis based on existing research, as a foundation for further research the mechanisms of epigenetic regulatory in erythropoiesis.

Erythropoiesis↗
PubMed2025

Prediction of gene expression using histone modification patterns extracted by Particle Swarm Optimization.

MOTIVATION: Histone modifications play an important role in transcription regulation. Although the general importance of some histone modifications for transcription regulation has been previously established, the relevance of others and their interaction is subject to ongoing research. By training Machine Learning models to predict a gene's expression and explaining their decision making process, we can get hints on how histone modifications affect transcription. In previous studies, trained models were either hardly explainable or the models were trained solely on the abundance of histone modifications. Based on other studies, which used histone modification patterns, rather than their abundance, to identify potential regulatory elements, we hypothesize the histone modification pattern in a gene's promoter to be more predictive for gene expression. We used an optimization algorithm to extract predictive histone modification profiles. RESULTS: Our algorithm called PatternChrome achieved an average area under curve (AUC) score of 0.9029 over 56 samples for binary classification, outperforming all previous algorithms for the same task. We explained the models decisions to deduce the effect of specific features, certain histone modifications or promoter positions on transcription regulation. Although the predictive histone modification patterns were extracted for each sample separately, they can be used to predict gene expression in other samples, implying that the created patterns are largely generalizable. Interestingly, the impact of histone modifications on gene regulation appears predominantly indifferent to cellular specificity. Through explanation of the classifier's decisions, we substantiate established literature knowledge while concurrently revealing novel insights into the intricate landscape of transcriptional regulation via histone modification. AVAILABILITY AND IMPLEMENTATION: The code for the PatternChrome algorithm, the scripts for the analyses and the required data can be found at (https://gitlab.gwdg.de/MedBioinf/generegulation/patternchrome).

Humans↗
PubMed2025

Multiomics Reveal Associations Between CpG Methylation, Histone Modifications and Transcription in a Species That has Lost DNMT3, the Colorado Potato Beetle.

Insects display exceptional phenotypic plasticity, which can be mediated by epigenetic modifications, including CpG methylation and histone modifications. In vertebrates, both are interlinked and CpG methylation is associated with gene repression. However, little is known about these regulatory systems in invertebrates, where CpG methylation is mainly restricted to gene bodies of transcriptionally active genes. A widely conserved mechanism involves the co-transcriptional deposition of H3K36 trimethylation and the targeted methylation of unmethylated CpGs by the de novo DNA methyltransferase DNMT3. However, DNMT3 has been lost multiple times in invertebrate lineages raising the question of how the links between CpG methylation, histone modifications and gene expression are affected by its loss. Here, we report the epigenetic landscape of Leptinotarsa decemlineata, a beetle species that has lost DNMT3 but retained CpG methylation. We combine RNA-seq, enzymatic methyl-seq and CUT&Tag to study gene expression, CpG methylation and patterns of H3K36me3 and H3K27ac histone modifications on a genome-wide scale. Despite the loss of DNMT3, H3K36me3 mirrors CpG methylation patterns. Together, they give rise to signature profiles for expressed and not expressed genes. H3K27ac patterns show a prominent peak at the transcription start site that is predictive of expressed genes irrespective of their methylation status. Our study provides new insights into the evolutionary flexibility of epigenetic modification systems that urge caution when generalizing across species.

Animals↗
PubMed2025

Proteins driving liquid-liquid phase separation and histone modifications cooperatively associate with chromatin looping and transcriptional regulation.

BACKGROUND: Although liquid-liquid phase separation (LLPS) proteins are known to participate in genome organization and transcriptional regulation through the formation of biomolecular condensates, their functional interplay with other regulatory proteins and histone modifications in chromatin loop formation remains poorly characterized. By combining Hi-C chromatin interaction data with ChIP-seq profiles of 12, 27, and 24 LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively, we identified chromatin loops associated with LLPS proteins and systematically analysed patterns of cooperative protein binding and histone modification enrichment within these loop-associated peaks. RESULTS: We identified 162, 313, and 431 chromatin loops associated with LLPS proteins in GM12878, K562, and HepG2 cell lines, respectively. These loops were relatively small in size and predominantly anchored at enhancer regions. Examination of cooperative binding of proteins within loop-associated peaks revealed that transcriptional repressor IKZF1, HDAC1, and SAP130 most frequently co-localized with LLPS proteins in GM12878, K562, and HepG2 cells, respectively. Further analysis of histone modification enrichment patterns revealed that active histone modifications, such as H3K4me2, H3K4me3, H3K9ac, and H3K27ac, co-localized at loop-associated peaks, with H3K4me1 exhibiting additional specific co-localization with these four histone modifications at enhancer-localized loop-associated peaks. Notably, bivalent chromatin domains where H3K27me3 co-localized with active histone modifications were identified at promoter-localized loop-associated peaks in HepG2 cells, and elevated H3K27me3 occupancy at these peaks was associated with transcriptional repression of target genes. Moreover, quantitative RNA-seq analysis revealed that the expression of target genes associated with enhancer-promoter loops was correlated with both the binding of LLPS proteins and the enrichment patterns of histone modifications within their ChIP-seq peaks at loop anchors. CONCLUSIONS: Our study suggests that LLPS proteins may cooperate with transcriptional repressors to facilitate chromatin looping. Furthermore, local enrichment of histone modifications at loop-associated peaks provides additional regulatory control over chromatin architecture and gene transcription.

Humans↗
PubMed2025

Single-cell multi-omic detection of DNA methylation and histone modifications reconstructs the dynamics of epigenomic maintenance.

DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi2-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.

DNA Methylation↗
PubMed2026

SET domain bifurcated histone lysine methyltransferase 1 regulates histone modification and DNA damage response during zygotic genome activation in pigs.

SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a key epigenetic regulator that catalyzes histone H3 lysine 9 trimethylation (H3K9me3), a mark essential for transcriptional repression and heterochromatin formation. Here, we investigated the role of SETDB1 during zygotic genome activation (ZGA) in porcine embryos. SETDB1 knockdown (KD) was induced by microinjecting double-stranded RNA (dsRNA), and its impact on early embryonic development was evaluated. SETDB1 KD decreased H3K9me3 levels, markedly increased H3K9ac, and downregulated ZGA-associated genes. These epigenetic alterations were accompanied by impaired cleavage, reduced blastocyst formation, and a lower total cell number. Upon etoposide-induced DNA double-strand breaks, SETDB1 KD embryos showed reduced expression of key DNA repair proteins, failed to efficiently restore DNA integrity, and exhibited increased apoptosis, indicating a compromised DNA damage response and repair process. SETDB1 KD also reduced HDAC3 expression, suggesting that SETDB1 may regulate HDAC3 to maintain histone acetylation balance. Consistently, HDAC3 inhibition increased H3K9ac, decreased H3K9me3, and reduced SETDB1 protein levels, supporting a reciprocal regulatory relationship. Together, these findings indicate that SETDB1 is important for porcine embryonic development by coordinating histone modifications and safeguarding genomic integrity during ZGA, and they suggest that the interplay between SETDB1 and HDAC3 constitutes a potentially important epigenetic axis for proper histone modification dynamics and developmental competence.

Animals↗
PubMed2025

Altered histone modifications in Aedes aegypti following Rift Valley fever virus exposure.

When arthropod-borne viruses (arboviruses) are delivered to vector mosquitoes in an infectious bloodmeal, viral components interact with host proteins to hijack cells and initiate replication. The extent to which arbovirus infection alters mosquito host transcriptional and genomic regulatory processes is currently unknown. We hypothesized that histone modifications would be altered in mosquitoes exposed to Rift Valley fever virus (RVFV MP12, Phlebovirus riftense, family Phleboviridae). We interrogated transcriptome and chromatin landscapes in Aedes aegypti midguts by performing Cleavage Under Targets and Release Using Nuclease (CUT&RUN), using H3K27ac and H3K9me3 marks. Altered H3K27ac marks were identified following RVFV MP12 exposure, as well as upon bloodfeeding alone. It took several days for differential H3K27ac marks to be associated with differentially expressed genes (DEGs) in RVFV-exposed midguts. H3K27ac peaks showed progressive depletion as infection progressed. Gene set enrichment analysis revealed that immune response transcripts were enriched at 1 and 3 dpf (days post-feeding) but depleted by 7 dpf. Hedgehog/Gli (glioma-associated oncogene homolog) signaling pathway transcripts were depleted, indicating possible viral manipulation of cellular polarization. Moreover, at 7 dpf, 7 of 102 DEGs were proximal to differentially acetylated sites in a pattern expected to favor viral propagation. However, one transcript coding for an antiviral effector (LysM-TLDc domain protein) showed significant depletion of both H3K9me3 and H3K27ac marks. Analysis of midguts after a non-infectious bloodmeal versus sugar-fed controls revealed global changes to H3K27ac and H3K9me3 marks during and following the period of bloodmeal digestion. Differential H3K27ac marks were proximal to one quarter of all DEGs at 1 dpf, consistent with an important role of H3K27ac in bloodmeal digestion. These results demonstrate that H3K27ac and H3K9me3 patterns are altered upon virus exposure in a complex interplay that favors viral replication but is also countered by host responses to limit replication.

ChIP-Seq↗
PubMed2026

Genome-wide profiling of histone modifications and transcription factor binding at single-cell resolution by DeChIC-seq.

Mapping of protein-DNA interactions at single-cell resolution remains a central challenge in epigenomics, particularly for transcription factors (TFs), whose sparse binding limits reliable detection. Here, we establish DeChIC-seq (DNA Deaminase-based Chromatin Immuno-Conversion sequencing), a conversion-based strategy that uses a protein A-DddAtox fusion to directly record protein-DNA interactions by inducing localized C-to-U conversions near antibody-bound chromatin. Retaining genome-wide background sequence information without immunoprecipitation, DeChIC-seq enables profiling of histone modifications and sensitive detection of TF binding. Integration with single-cell whole-genome amplification extends DeChIC-seq to single-cell applications (scDeChIC-seq), enabling chromatin profiling of individual cells. Applied to mouse embryogenesis, scDeChIC-seq resolves lineage-specific chromatin states through profiling of H3K4me3, CTCF, and RAD21 and sensitively detects TF binding, including that of NR5A2, TFAP2C, and KLF5, from extremely limited blastomere inputs. This underscores its strong potential for detecting TF-binding sites in scarce biological samples. DeChIC-seq establishes a conversion-based framework for chromatin profiling that enables mechanistic dissection of TF-driven gene regulation across rare cells, developmental systems, and disease contexts.

Animals↗
PubMed2026

TRIM28 regulates the G2/M transition via histone modification and DNA damage repair during mouse oocyte meiosis.

TRIM28, a member of the tripartite motif (TRIM) family, functions as a transcriptional coregulator involved in maintaining genome stability during mitosis. In this study, we explored the role of TRIM28 in mouse oocyte meiotic maturation, where transcriptional activity is barely detectable. We found that TRIM28 was constitutively expressed during the early stages of oocyte meiotic maturation, with predominant nuclear localization in germinal vesicle (GV)-stage oocytes. TRIM28 depletion caused defective germinal vesicle breakdown (GVBD), but oocytes that successfully underwent GVBD displayed unimpaired first polar body (PB1) extrusion. TRIM28 depletion impaired CDK1 activity and reduced cyclin B1 levels, leading to a delay in the G2/M transition. This delay might be caused by altered levels of HDAC2-mediated H4K12ac and H3K4me2-modulated H3K9me2 in nonsurrounded nucleolus (NSN)-type GV oocytes, which decreased transcription activity. Additionally, TRIM28-depleted oocytes exhibited elevated γ-H2A.X expression, accompanied by aberrant expression of CHK1 and CHK2, as well as dysregulated expression of RAD51, which collectively contributed to GVBD failure in mouse oocytes. In conclusion, our findings indicate that TRIM28 participates in the regulation of the G2/M transition during mouse oocyte meiotic maturation, acting through the modulation of histone modifications and DNA damage repair.

Animals↗
PubMed2025

Genome-Wide Profiling of Histone Modifications in Fission Yeast Using CUT&Tag.

Eukaryotic DNA is organized in the nucleus in the form of chromatin. Nucleosomes, the fundamental unit of chromatin, are subject to many posttranslational modifications (PTMs) as well as compositional variations through incorporation of histone variants. These alterations play important roles in regulation of genome structure and activity. Genome-wide profiling of these regulatory features is essential for understanding of genome function. Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) is a widely used method to assay genome-wide localization in fission yeast but suffers from the requirement for a large amount of input chromatin, antibodies, and a cumbersome experimental pipeline. New methods such as Cleavage Under Targets and Tagmentation (CUT&Tag), which combine the specificity of targeted cleavage and adapter insertion with the sensitivity of next-generation sequencing, enable identification and characterization of various epigenetic marks affording low input requirement as well as more streamlined protocols. However, these approaches have not been adapted for use in fission yeast, Schizosaccharomyces pombe. Here, we describe an adapted CUT&Tag protocol for epigenomic profiling in fission yeast using the heterochromatin-associated histone H3K9 methylation PTM for benchmarking.

Schizosaccharomyces↗
PubMed2024

Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Animals↗
PubMed1979

Histone modifications in simian virus 40 and in nucleoprotein complexes containing supercoiled viral DNA.

Simian virus (SV40) nucleoprotein complexes containing circular supercoiled viral DNA were extracted from infected cells and purified by differential centrifugation. The protein content of these complexes was compared by electrophoresis on 15% acrylamide gels with the protein content of purified SV40 virions and with histones from virus-infected cells. The electrophoretic patterns of histones from each of the sources revealed several major differences. SV40 virions contained histones H3, H2B, H2A, and H4 but not H1. Nucleoprotein complexes and host cells contained all five major histone groups. Relative to cellular histones, virion and nucleoprotein complex histones were enriched 15 to 40% in histones H3 and H4. In addition to the major classes of histones, several subfractions of histones H1, H3, and H4 were observed in acrylamide gels of proteins from SV40 virions and viral nucleoprotein complexes. Acetate labeling experiments indicated that each subfraction of histones H3 and H4 had a different level of acetylation. The histones from SV40 virions and nucleoprotein complexes were acetylated to significantly higher levels than those of infected host cells. No apparent differences in phosphorylation of the major histone groups were observed.

Acetylation↗
PubMed2026

Improved spike-in normalization clarifies the relationship between active histone modifications and transcription.

Spike-in normalization enables quantitative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) signal. Here we introduce a robust dual spike-in normalization approach for ChIP-seq (ChIP-wrangler), optimize parameters and verify its accuracy in quantifying changes in ChIP-seq signal and detecting technical artifacts. We use ChIP-wrangler to revisit recent claims that active histone marks depend on transcription. We show that acute depletion of RNA polymerase II (RNAPII) has a modest impact on H3K27ac levels, with only 6% of peaks significantly changing after RNAPII depletion, indicating that histone acetylation maintenance is not entirely dependent on ongoing transcription. Promoters and enhancers are differentially affected, with 82% of decreasing acetylation peaks located at promoter-distal elements with enhancer-related motifs. ChIP-wrangler provides increased rigor and 'guardrails' for successful spike-in normalization and, as applied here, refines the understanding of crosstalk between RNAPII activity and transcription-associated histone marks.

Histones↗
PubMed2025

Integrative analysis of gene expression and histone modifications for DES, DSP, GJA1 and SMOC2 in adipose tissue reveals potential relationship to cardiometabolic health.

BACKGROUND: Adipose tissue influences cardiometabolic health through its endocrine activity and its role in regulating inflammation, lipid metabolism, and cardiovascular function. The expression of cardiac-associated genes within adipose tissue may reflect or contribute to cardiometabolic risk, yet this relationship remains poorly understood. This study investigates the expression profiles of the cardiac function associated genes GJA1, DES, DSP and SMOC2 in human adipose tissue, and analyses their associations with cardiometabolic traits. Additionally, we explore epigenomic mechanisms that may underlie their differential gene expression. METHODS: Expression profiling and functional enrichment analyses were conducted to identify depot-specific cardiac gene expression patterns. Quantitative PCR validated gene expression in paired subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples from 78 individuals with obesity. Gene expression was further validated in three independent cohorts (N = 1,548 total). Associations with clinical traits were assessed using Spearman correlations and multivariate linear regression, adjusted for age, sex, and BMI. Integration with transcriptomic and proteomic datasets publicly available from the Adipose Tissue Knowledge Portal was performed to strengthen clinical relevance. Epigenomic profiling using genome-wide ChIP-seq for histone marks (H3K4me3, H3K4me1, H3K27ac, H3K27me3) was conducted in paired SAT and OVAT samples from five individuals. RESULTS: DES, DSP, GJA1, and SMOC2 were significantly upregulated in OVAT compared to SAT. DES, DSP, and SMOC2 showed consistent expression patterns across all cohorts, while GJA1 exhibited context-dependent regulation. Gene expression in SAT was negatively correlated with cardiometabolic traits, including blood pressure, insulin resistance, and liver function markers. These associations were confirmed by regression analysis and supported by publicly available multi-omics data. Epigenetic analyses revealed OVAT-specific enrichment of active histone marks and reduced repressive marks, supporting higher differential transcriptional activity in OVAT. CONCLUSIONS: Depot-specific gene expression of DES, DSP, and SMOC2 in adipose tissue is robustly linked to cardiometabolic traits and supported by distinct epigenetic landscapes in OVAT vs SAT, highlighting their potential as novel biomarkers for cardiometabolic health.

Humans↗
PubMed2027

Genomic Profiling of Chromatin State Using CUT&Tag.

Alterations in chromatin state, mediated through histone modifications and the incorporation of histone variants, are fundamental to establishing transcriptional networks and cell identity. Recent advances in low-input epigenome profiling methods, such as CUT&Tag and CUT&RUN, have enabled the study of chromatin states from very limited starting materials. In this chapter, we describe procedures for generating CUT&Tag libraries to profile histone modifications and histone variants in early-developing zebrafish embryos.

Animals↗