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At least 19 recordsLinked to original sources
PubMed2025

Quantitative Profiling of Histone Variants and Posttranslational Modifications by Tandem Mass Spectrometry in Arabidopsis.

Histone dynamics constitute an important layer of gene regulations associated with development and growth in multicellular eukaryotes. They also stand as key determinants of plant responses to environmental changes. Histone dynamics include the exchange of histone variants as well as post-translational modifications of their amino acid residues (such as acetylation and mono/di/trimethylation), commonly referred to as histone marks. Investigating histone dynamics with a focus on combinatorial changes occurring at their residues will greatly help unravel how plants achieve phenotypic plasticity.Mass spectrometry (MS) analysis offers unequaled resolution of the abundance of histone variants and of their marks. Indeed, relative to other techniques such as western blot or genome-wide profiling, this powerful technique allows quantifying the relative abundances of histone forms, as well as revealing coexisting marks on the same histone molecule. Yet, while MS-based histone analysis has proven efficient in several animals and other model organisms, this method stands out as more challenging in plants. One major challenge is the isolation of sufficient amounts of pure, high-quality histones, likely rendered difficult by the presence of the cell wall, for sufficiently deep and resolutive identification of histone species.In this chapter, we describe a straightforward MS-based proteomic method, implemented to characterize histone marks from Arabidopsis thaliana seedling tissues and cell culture suspensions. After acid extraction of histones, in vitro propionylation of free lysine residues, and digestion with trypsin, a treatment at highly basic pH allows obtaining sharp spectral signals of biologically relevant histone peptide forms.The method workflow described here shall be used to measure changes in histone marks between Arabidopsis thaliana genotypes, along developmental time-courses, or upon various stresses and treatments.

Histones↗
PubMed2026

Histone variant H2A.J is an epigenetic regulator of metastasis in lung adenocarcinoma.

Metastasis is a major contributor to poor patient survival in lung adenocarcinoma (LUAD); however, the underlying mechanisms remain incompletely understood. Unlike tumorigenesis-associated mutations, recurrent genetic alterations specifically linked to metastasis have not been identified, suggesting that epigenetic mechanisms may play a key role. In this study, we report that histone H2A variant H2A.J expression is significantly down-regulated in LUAD, and that low H2A.J levels are associated with unfavorable survival outcomes. Functional assays revealed that H2A.J overexpression suppresses cancer cell invasion and metastatic potential by modulating the expression of metastasis-associated genes, including TMEM158. Mechanistically, H2A.J is deposited in the promoter region of TMEM158, where it alters the local chromatin status to suppress transcriptional activity. Taken together, our findings suggest that H2A.J functions as an epigenetic suppressor of metastasis in LUAD and highlights its potential as both a prognostic biomarker and a therapeutic target to metastatic progression.

Humans↗
PubMed2025

Trypanosomatid histones: the building blocks of the epigenetic code of highly divergent eukaryotes.

Histones play a fundamental role in eukaryotic organisms not only as scaffolding proteins in DNA packaging but also in regulating gene expression. They constitute the protein reel around which DNA wraps forming nucleosomes. This initial packing gives rise to the chromatin fiber which is next folded into three-dimensional arrangements. Additionally, histones have expanded their functions through the emergence of histone variants which have specialized purposes and can deeply affect chromatin organization and dynamics. Moreover, both canonical histones and histone variants comprise the building blocks of the histone code by being targets of different post-translational modifications (PTMs) that occur in a highly regulated manner both in place and time. Most of the above-mentioned about chromatin organization is conserved among eukaryotes. However, trypanosomatid histones have many peculiarities that entail a special description. In this review, we compile the current knowledge of canonical core histones, histone variants, and their PTMs in trypanosomatids. We highlight the similarities and differences between histone variants and their canonical counterparts in trypanosomatids, and we compare them with those from model organisms. Finally, we discuss the crosstalk between different histone marks and their genomic distribution underlying the uniqueness of trypanosomatids.

Histones↗
PubMed2026

A GWAS-derived histone H4 variant linked to ear row number reveals functional insights into the maize ZmHistone gene family.

Ear row number (ERN) is a major yield determinant in maize and a key target for breeding of high-yielding varieties. This study utilized a multi-parent population (MPP) of 780 recombinant inbred lines (RILs) derived from seven inbred lines across three environments. Genotyping-by-sequencing (GBS) of the MPP yielded 638,646 high-quality SNPs. Using genome-wide association study (GWAS), we detected 80 significant SNPs including S2-15316355 and S4-224453431, which were consistently detected in all environments and best linear unbiased prediction (BLUP) analysis. A linkage disequilibrium-defined ±20 kb window around these two lead SNPs contained three positional candidate genes: Zm00001eb072840, Zm00001eb072850 and Zm00001eb202890. Zm00001eb072850 (ZmHistone12), a histone H4 variant, was prioritized for hypothesis-driven follow-up because the lead SNP lies within its coding sequence and the gene is expressed in ear-related tissues. Additionally, we identified 91 ZmHistone genes in the maize genome and described their phylogeny, promoter motif and expression patterns. Public transcriptome and qRT-PCR analysis in seven parental lines provide descriptive evidence of Histone variant genes in maize ear development. These results suggest a potential involvement of chromatin-associated regulation of ERN in maize and provide a foundation for future functional validation.

Ear development↗
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↗
PubMed2026

Phosphorylation of BigH1 regulates its expression pattern and promotes embryonic development.

Metazoan genomes typically encode several linker histone variants, often expressed in a tissue- or developmental stage-specific manner. The Drosophila melanogaster genome contains only two linker histone variants: H1 is present in somatic cells, while BigH1 substitutes H1 in the germline and early embryos. In the early stages of embryogenesis, BigH1 is replaced by H1 in the chromatin of somatic cells, contributing to the initiation and maintenance of the zygotic gene expression program. Nevertheless, the molecular mechanism of this exchange and the possible functions of post-translational modifications of BigH1 in this process remain elusive. Here, we identify phosphorylation as a key post-translational regulator of BigH1 dynamics. Using proteomics and targeted mutagenesis of the endogenous BigH1 locus, we show that the loss of N-terminal phosphorylation results in persistent retention of BigH1 in somatic nuclei throughout embryogenesis, indicating a failure in BigH1 turnover. In contrast, disruption of C-terminal phosphorylation does not markedly affect BigH1 clearance but increases defects during early nuclear divisions and compromises embryonic development, particularly under suboptimal conditions. Together, these findings demonstrate that domain-specific phosphorylation differentially regulates BigH1 function, coordinating its early embryonic role with its subsequent removal from the chromatin.

BigH1↗
PubMed2026

Molecular mechanisms of plant thermal response: from signal transduction and epigenetic regulation to signaling integration.

Global warming intensification elevates heat stress to one of the major threats to crop productivity. This review synthesizes recent advances in understanding the mechanisms governing plant responses to both moderate and acute heat stress, with a focus on the integration of epigenetic regulation and signaling networks that underpin thermal adaptation. This review highlights how transcription factors PHYTOCHROME-INTERACTING FACTOR 4 (PIF4, during thermomorphogenesis) and HEAT SHOCK FACTOR A1s (HSFA1s, in heat shock responses) orchestrate plant adaptive growth through crosstalk among light, circadian, and hormone signaling pathways. Importantly, epigenetic mechanisms, including histone variant H2A.Z dynamics and histone modification reprogramming, function as central regulators of thermal plasticity. Key among these processes are HSFA2-mediated chromatin remodeling and small interfering RNA (siRNA)-dependent control of transgenerational thermomemory. Despite this progress, fundamental questions persist regarding temperature sensing, HSFA1s activation dynamics, and stress signal integration. Multi-omics and synthetic biology approaches are proposed to be pivotal in deciphering conserved principles of plant thermal resilience, ultimately providing a theoretical foundation and molecular breeding strategies for climate-smart crops.

Epigenesis, Genetic↗
PubMed2023

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.

BACKGROUND: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood. RESULTS: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate. CONCLUSIONS: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3.

Animals↗
PubMed2025

Characterization of oncohistone H2B variants in Schizosaccharomyces pombe reveals a key role of H2B monoubiquitination deficiency in genomic instability by altering gene expression.

Various amino acid substitutions commonly occur at one residue of a histone in human cancers, but it remains unclear whether these histone variants have distinct oncogenic effects and mechanisms. Our previous modeling study in the fission yeast Schizosaccharomyces pombe demonstrated that the oncohistone mutants H2BG52D, H2BD67N, and H2BP102L cause the homologous recombination defects and genomic instability by compromising H2B monoubiquitination (H2Bub). However, it is unknown whether other amino acid changes at the H2B-Gly52/Asp67/Pro102 residues influence H2Bub levels and whether they cause genomic instability by altering H2Bub-regulated gene expression. Here, we construct diverse oncomutants at the sole H2B gene htb1-Gly52/Asp67/Pro102 sites in S. pombe and study their impacts on genotoxic response, H2Bub levels, and gene expression. Interestingly, the oncomutants htb1-G52D, htb1-D67N, and htb1-P102L exclusively exhibit significant genotoxic sensitivity, reduced H2Bub levels, and altered gene expression. These defects can be rescued by restoring H2Bub levels with the deletion of the H2B deubiquitinase ubp8+. These strong genetic correlations suggest that H2Bub deficiency plays a determinant role in the genomic instability of htb1-Gly52/Asp67/Pro102 oncomutants and that the alteration of gene expression due to reduced H2Bub levels is a novel mechanism underlying the genomic instability caused by htb1-G52D, htb1-D67N, and htb1-P102L oncomutations.

Schizosaccharomyces↗
PubMed2025

Functions of TIP60/NuA4 Complex Subunits in Cell Differentiation.

The TIP60/NuA4 complex is a large, multifunctional histone acetyltransferase assembly of ~1.7 megadaltons, composed of 17-20 subunits, which plays a central role in epigenetic regulation. Through recognition of H3K4me3 by the ING3 reader, TIP60/NuA4 is recruited to sites of active transcription, where it remodels chromatin to regulate gene expression. Its activities include histone acetylation, histone variant exchange, transcriptional co-activation, and regulation of the cell cycle and apoptosis. In this review, we examine how altered subunit levels or mutations impact the chromatin structure and transcriptional activity, and how these changes influence differentiation across diverse cell types. We emphasize the molecular mechanisms by which TIP60/NuA4 shapes lineage specification, including histone H2A and H4 acetylation by the KAT5 catalytic subunit, H2A.Z incorporation by EP400, and interactions with transcription factors such as MyoD, PPARγ, and Myc. By integrating mechanistic and functional insights, we highlight how TIP60/NuA4 acts as a central epigenetic hub in differentiation and contributes to proper developmental transitions.

Humans↗
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↗
PubMed2026

Cohesin prevents local mixing of condensed euchromatic domains in living human cells.

The human genome is folded into chromatin loops by the cohesin complex, forming functional chromatin domains that underlie transcription and DNA replication/repair. However, how cohesin organizes these domains in living cells, especially in active euchromatin, remains elusive. Here, to address this question, we combined single-nucleosome imaging/tracking and super-resolution three-dimensional structured illumination microscopy with euchromatin-specific labeling of histone variant H3.3. Using this nanoscopic approach, we revealed that euchromatin forms condensed domains that are constrained by cohesin-mediated loops. This organization refines the classical view of euchromatin as largely open, in line with emerging evidence. Transcription machinery appears to be located near the condensed domain surfaces/borders. Cohesin loss increased nucleosome-level fluidity within these domains without altering their overall compaction, leading to local mixing of domains and compromising transcriptional insulation. These findings suggest a physical role of cohesin in maintaining the integrity of condensed euchromatic domains and ensuring proper higher-order regulation of gene expression.

Humans↗
PubMed2025

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation during the mammalian parental-to-zygote transition is poorly understood. To address this, we generated a CENP-A-mScarlet mouse model that revealed sex-specific dynamics: mature sperm retain 10% of the CENP-A levels present in MII oocytes. However, this difference is resolved in zygotes prior to the first mitosis, using maternally inherited cytoplasmic CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on the asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in both pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization function impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts as a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.

Animals↗
PubMed2026

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

X-linked Nuclear Protein↗
PubMed2025

DIS3 licenses B cells for plasma cell differentiation in humans.

DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.

Humans↗
PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗
PubMed2025

Two CENH3 paralogs in the green alga Chlamydomonas reinhardtii have a redundantly essential function and associate with ZeppL-LINE1 elements.

Centromeres in eukaryotes are defined by the presence of histone H3 variant CENP-A/CENH3. Chlamydomonas encodes two predicted CENH3 paralogs, CENH3.1 and CENH3.2, that have not been previously characterized. We generated peptide antibodies to unique N-terminal epitopes for each of the two predicted Chlamydomonas CENH3 paralogs as well as an antibody against a shared CENH3 epitope. All three CENH3 antibodies recognized proteins of the expected size on immunoblots and had punctate nuclear immunofluorescence staining patterns. These results are consistent with both paralogs being expressed and localized to centromeres. CRISPR-Cas9-mediated insertional mutagenesis was used to generate predicted null mutations in either CENH3.1 or CENH3.2. Single mutants were viable but cenh3.1 cenh3.2 double mutants were not recovered, confirming that the function of CENH3 is essential. We sequenced and assembled two chromosome-scale Chlamydomonas genomes from strains CC-400 and UL-1690 (a derivative of CC-1690) with complete centromere sequences for 17/17 and 14/17 chromosomes respectively, enabling us to compare centromere evolution across four isolates with near complete assemblies. These data revealed significant changes across isolates between homologous centromeres including mobility and degeneration of ZeppL-LINE1 (ZeppL) transposons that comprise the major centromere repeat sequence in Chlamydomonas. We used cleavage under targets and tagmentation (CUT&Tag) to purify and map CENH3-bound genomic sequences and found enrichment of CENH3-binding almost exclusively at predicted centromere regions. An interesting exception was chromosome 2 in UL-1690, which had enrichment at its genetically mapped centromere repeat region as well as a second, distal location, centered around a single recently acquired ZeppL insertion. The CENH3-bound regions of the 17 Chlamydomonas centromeres ranged from 63.5 kb (average lower estimate) to 175 kb (average upper estimate). The relatively small size of its centromeres suggests that Chlamydomonas may be a useful organism for testing and deploying artificial chromosome technologies.

Chlamydomonas reinhardtii↗
PubMed2026

MacroH2A2-Enriched Domains Are Largely Stable Across the Cell Cycle but Focally Displaced at Mitotic Regulatory Elements.

The macroH2A variants mH2A1 and mH2A2 are structurally similar but not identical. Our previous study demonstrated that mH2A1 is reloaded during cell-cycle progression, but whether mH2A2 follows similar dynamics has remained unclear. Here, we used native ChIP-seq in synchronized Huh-7 cells to profile both variants at G1/S and G2/M. Although mH2A1- and mH2A2-enriched domains overlapped extensively, mH2A2 domains were largely stable across the cell cycle, in sharp contrast to the dynamic reloading of mH2A1. Only a small subset of mH2A2 domains showed phase-specific deposition or displacement. Among these, G1/S-unique mH2A2 domains were preferentially located in the active A compartment and coincided with reduced chromatin accessibility at binding sites for cell-cycle regulators. These G1/S-unique domains co-localize with genes involved in mitotic progression within the same A compartment, suggesting potential regulatory roles in both chromatin organization and transcriptional regulation. These findings refine the classical view of macroH2A variants as static repressive marks: mH2A2 is not entirely static, but its cell-cycle dynamics are far more restricted than those of its paralog mH2A1, occurring only at a small subset of genomic loci, with a regulatory logic distinct from that of mH2A1.

Histones↗