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In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity., The order of DNA methylation and histone modifications during transcription remained unclear. Here the authors show that HMGA2 induces DNA nicks at TGFB1-responsive genes, promoting nucleosome incorporation containing γ-H2AX, which is required for repair-mediated DNA demethylation and transcription.

Sessile plants possess an assembly of signaling pathways that perceive and transmit environmental signals, ultimately resulting in transcriptional reprogramming. Histone is a key feature of chromatin structure. Numerous histone-modifying proteins act under different environmental stress conditions to help modulate gene expression. DNA methylation and histone modification are crucial for genome reprogramming for tissue-specific gene expression and global gene silencing. Different classes of chromatin remodelers including SWI/SNF, ISWI, INO80, and CHD are reported to act upon chromatin in different organisms, under diverse stresses, to convert chromatin from a transcriptionally inactive to a transcriptionally active state. The architecture of chromatin at a given promoter is crucial for determining the transcriptional readout. Further, the connection between somatic memory and chromatin modifications may suggest a mechanistic basis for a stress memory. Studies have suggested that there is a functional connection between changes in nuclear organization and stress conditions. In this review, we discuss the role of chromatin architecture in different stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory.

Histone variants differ in amino acid sequence, expression timing and genomic localization sites from canonical histones and convey unique functions to eukaryotic cells. Their tightly controlled spatial and temporal deposition into specific chromatin regions is accomplished by dedicated chaperone and/or remodeling complexes. While quantitatively identifying the chaperone complexes of many human H2A variants by using mass spectrometry, we also found additional members of the known H2A.Z chaperone complexes p400/TIP60/NuA4 and SRCAP. We discovered JAZF1, a nuclear/nucleolar protein, as a member of a p400 sub-complex containing MBTD1 but excluding ANP32E. Depletion of JAZF1 results in transcriptome changes that affect, among other pathways, ribosome biogenesis. To identify the underlying molecular mechanism contributing to JAZF1&rsquo, s function in gene regulation, we performed genome-wide ChIP-seq analyses. Interestingly, depletion of JAZF1 leads to reduced H2A.Z acetylation levels at &gt, 1000 regulatory sites without affecting H2A.Z nucleosome positioning. Since JAZF1 associates with the histone acetyltransferase TIP60, whose depletion causes a correlated H2A.Z deacetylation of several JAZF1-targeted enhancer regions, we speculate that JAZF1 acts as chromatin modulator by recruiting TIP60&rsquo, s enzymatic activity. Altogether, this study uncovers JAZF1 as a member of a TIP60-containing p400 chaperone complex orchestrating H2A.Z acetylation at regulatory regions controlling the expression of genes, many of which are involved in ribosome biogenesis.

In response to DNA double-strand breaks (DSBs), chromatin modifications orchestrate DNA repair pathways thus safeguarding genome integrity. Recent studies have uncovered a key role for heterochromatin marks and associated factors in shaping DSB repair within the nucleus. In this review, we present our current knowledge of the interplay between heterochromatin marks and DSB repair. We discuss the impact of heterochromatin features, either pre-existing in heterochromatin domains or de novo established in euchromatin, on DSB repair pathway choice. We emphasize how heterochromatin decompaction and mobility further support DSB repair, focusing on recent mechanistic insights into these processes. Finally, we speculate about potential molecular players involved in the maintenance or the erasure of heterochromatin marks following DSB repair, and their implications for restoring epigenome function and integrity.

Simple Summary The structural unit of chromatin is the nucleosome that is composed of DNA wrapped around a core of eight histone proteins. Histone variants can replace 'standard' histones at specific sites of the genome. Thus, histone variants modulate all functions in the context of chromatin, such as gene expression. Here, we provide a concise review on a group of histone variants termed macroH2A. They contain two additional domains that contribute to their increased size. We discuss how these domains mediate molecular functions in normal cells and the role of macroH2As in gene expression and cancer. The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.

Histones are the major proteinaceous component of chromatin in eukaryotic cells and an important part of the epigenome, affecting most DNA‐related events, including transcription, DNA replication, and chromosome segregation. The properties of histones are greatly influenced by their post‐translational modifications (PTMs), over 200 of which are known today. Given this large number, researchers need sophisticated methods to study histone PTMs comprehensively. In particular, mass spectrometry (MS)−based approaches have gained popularity, allowing for the quantification of dozens of histone PTMs at once. Using these approaches, even the study of co‐occurring PTMs and the discovery of novel PTMs become feasible. The success of MS‐based approaches relies substantially on obtaining pure and well‐preserved histones for analysis, which can be difficult depending on the source material. Caenorhabditis elegans has been a popular model organism to study the epigenome, but isolation of pure histones from these animals has been challenging. Here, we address this issue, presenting a method for efficient isolation of pure histone proteins from C. elegans at good yield. Further, we describe an MS pipeline optimized for accurate relative quantification of histone PTMs from C. elegans. We alkylate and tryptically digest the histones, analyze them by bottom‐up MS, and then evaluate the resulting data by a C. elegans−adapted version of the software EpiProfile 2.0. Finally, we show the utility of this pipeline by determining differences in histone PTMs between C. elegans strains that age at different rates and thereby achieve very different lifespans. © 2020 The Authors. Basic Protocol 1: Large‐scale growth and harvesting of synchronized C. elegans Basic Protocol 2: Nuclear preparation, histone extraction, and histone purification Basic Protocol 3: Bottom‐up mass spectrometry analysis of histone PTMs and histone variants

The chromatin structure is dynamically regulated by many different modulators that post-translationally modify histones, replace canonical histones with histone variants, and unwind nucleosomal DNA, thereby modulating the accessibility of nucleosomal DNA and facilitating downstream DNA-templated nuclear processes. To understand how these modulators change the chromatin structure, it is essential to determine the 3D structures of chromatin modulators in complex with nucleosome. Here, we review the very recent progress in structural studies of some selected chromatin modulators in complex with nucleosome, including those of histone demethylases LSD1/2, some pioneer transcription factors, and the PWWP domain-containing protein LEDGF.

Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Here, we perform a genome-wide single guide RNA (sgRNA) screen for genes involved in ERV silencing and identify the GHKL ATPase protein Morc3 as a top-scoring hit. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions., Endogenous retroviruses (ERVs) compose a significant portion of mammalian genomes; however, how ERVs are regulated is not well known. Here the authors performed a genome-wide sgRNA screen to identify Morc3 as a mediator of ERV silencing. They show Morc3 associates with the H3.3 chaperone Daxx, and that loss of Morc3 leads to reduced H3.3 at ERVs.

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field.

International audience; Nucleosomes represent a challenge in regard to transcription. Histone eviction enables RNA polymerase II (RNAPII) progression through DNA, but compromises chromatin integrity. Here, we used the SNAP-tag system to distinguish new and old histones and monitor chromatin reassembly coupled to transcription in human cells. We uncovered a transcription-dependent loss of old histone variants H3.1 and H3.3. At transcriptionally active domains, H3.3 enrichment reflected both old H3.3 retention and new deposition. Mechanistically, we found that the histone regulator A (HIRA) chaperone is critical to processing both new and old H3.3 via different pathways. De novo H3.3 deposition is totally dependent on HIRA trimerization as well as on its partner ubinuclein 1 (UBN1), while antisilencing function 1 (ASF1) interaction with HIRA can be bypassed. By contrast, recycling of H3.3 requires HIRA but proceeds independently of UBN1 or HIRA trimerization and shows absolute dependency on ASF1–HIRA interaction. We propose a model whereby HIRA coordinates these distinct pathways during transcription to fine-tune chromatin states.; Les nucléosomes représentent un défi en ce qui concerne la transcription. L'éviction des histones permet la progression de l'ARN polymérase II (RNAPII) dans l'ADN, mais compromet l'intégrité de la chromatine. Ici, nous avons utilisé le système SNAP-tag pour distinguer les nouvelles et les anciennes histones et surveiller le réassemblage de la chromatine couplé à la transcription dans les cellules humaines. Nous avons découvert une perte dépendante de la transcription des anciens variants d'histones H3.1 et H3.3. Au niveau des domaines transcriptionnellement actifs, l'enrichissement en H3.3 reflétait à la fois la rétention de l'ancien H3.3 et le nouveau dépôt. Sur le plan mécanique, nous avons constaté que le chaperon du régulateur d'histone A (HIRA) est essentiel pour traiter à la fois le nouveau et l'ancien H3.3 par des voies différentes. Le dépôt de novo de H3.3 dépend totalement de la trimérisation de l'HIRA ainsi que de son partenaire l'ubinucléine 1 (UBN1), tandis que l'interaction de la fonction antisilencing 1 (ASF1) avec l'HIRA peut être contournée. En revanche, le recyclage du H3.3 nécessite l'AERH mais se fait indépendamment de la trimérisation de l'UBN1 ou de l'AERH et montre une dépendance absolue de l'interaction ASF1-AERH. Nous proposons un modèle dans lequel l'ARHI coordonne ces voies distinctes pendant la transcription pour affiner les états de la chromatine.

International audience; The epithelial-to-mesenchymal transition (EMT) is a physiological process activated during early embryogenesis, which continues to shape tissues and organs later on. It is also hijacked by tumor cells during metastasis. The regulation of EMT has been the focus of many research groups culminating in the last few years and resulting in an elaborate transcriptional network buildup. However, the implication of epigenetic factors in the control of EMT is still in its infancy. Recent discoveries pointed out that histone variants, which are key epigenetic players, appear to be involved in EMT control. This review summarizes the available data on histone variants’ function in EMT that would contribute to a better understanding of EMT itself and EMT-related diseases.

How a single genome can give rise to distinct cell types remains a fundamental question in biology. Mammals are able to specify and maintain hundreds of cell fates by selectively activating unique subsets of their genome. This is achieved, in part, by enhancers—genetic elements that can increase transcription of both nearby and distal genes. Enhancers can be identified by their unique chromatin signature, including transcription factor binding and the enrichment of specific histone post-translational modifications, histone variants, and chromatin-associated cofactors. How each of these chromatin features contributes to enhancer function remains an area of intense study. In this review, we provide an overview of enhancer-associated chromatin states, and the proteins and enzymes involved in their establishment. We discuss recent insights into the effects of the enhancer chromatin state on ongoing transcription versus their role in the establishment of new transcription programmes, such as those that occur developmentally. Finally, we highlight the role of enhancer chromatin in new conceptual advances in gene regulation such as condensate formation.

Sessile plants possess an assembly of signaling pathways that perceive and transmit environmental signals, ultimately resulting in transcriptional reprogramming. Histone is a key feature of chromatin structure. Numerous histone-modifying proteins act under different environmental stress conditions to help modulate gene expression. DNA methylation and histone modification are crucial for genome reprogramming for tissue-specific gene expression and global gene silencing. Different classes of chromatin remodelers including SWI/SNF, ISWI, INO80, and CHD are reported to act upon chromatin in different organisms, under diverse stresses, to convert chromatin from a transcriptionally inactive to a transcriptionally active state. The architecture of chromatin at a given promoter is crucial for determining the transcriptional readout. Further, the connection between somatic memory and chromatin modifications may suggest a mechanistic basis for a stress memory. Studies have suggested that there is a functional connection between changes in nuclear organization and stress conditions. In this review, we discuss the role of chromatin architecture in different stress responses and the current evidence on somatic, intergenerational, and transgenerational stress memory.

Current proteomic approaches disassemble and digest nucleosome particles, blurring readouts of the 'histone code'. To preserve nucleosome-level information, we developed Nuc-MS, which displays the landscape of histone variants and their post-translational modifications (PTMs) in a single mass spectrum. Combined with immunoprecipitation, Nuc-MS quantified nucleosome co-occupancy of histone H3.3 with variant H2A.Z (sixfold over bulk) and the co-occurrence of oncogenic H3.3K27M with euchromatic marks (for example, a >15-fold enrichment of dimethylated H3K79me2). Nuc-MS is highly concordant with chromatin immunoprecipitation-sequencing (ChIP-seq) and offers a new readout of nucleosome-level biology.

Nucleosome dynamics and properties are central to all forms of genomic activities. Among the core histones, H3 variants play a pivotal role in modulating nucleosome structure and function. Here, we focus on the impact of H3 variants on various facets of development. The deposition of the replicative H3 variant following DNA replication is essential for the transmission of the epigenomic information encoded in posttranscriptional modifications. Through this process, replicative H3 maintains cell fate while, in contrast, the replacement H3.3 variant opposes cell differentiation during early embryogenesis. In later steps of development, H3.3 and specialized H3 variants are emerging as new, important regulators of terminal cell differentiation, including neurons and gametes. The specific pathways that regulate the dynamics of the deposition of H3.3 are paramount during reprogramming events that drive zygotic activation and the initiation of a new cycle of development.

Background Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. Methods Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. Results Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. Conclusion The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

H2A.B is an evolutionarily distant histone H2A variant that accumulates on DNA repair sites, DNA replication sites, and actively transcribing regions in genomes. In cells, H2A.B exchanges rapidly in chromatin, but the mechanism has remained enigmatic. In the present study, we found that the H2A.B-H2B dimer incorporated within the nucleosome exchanges with the canonical H2A-H2B dimer without assistance from additional factors, such as histone chaperones and nucleosome remodelers. High-speed atomic force microscopy revealed that the H2A.B nucleosome, but not the canonical H2A nucleosome, transiently forms an intermediate “open conformation”, in which two H2A.B-H2B dimers may be detached from the H3-H4 tetramer and bind to the DNA regions near the entry/exit sites. Mutational analyses revealed that the H2A.B C-terminal region is responsible for the adoption of the open conformation and the H2A.B-H2B exchange in the nucleosome. These findings provide mechanistic insights into the histone exchange of the H2A.B nucleosome., 精子形成に重要なヒストンによるDNAの新たな折りたたみを解明. 京都大学プレスリリース. 2021-02-22.

Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

In light of our aging population, neurodegenerative disorders are becoming a tremendous challenge, that modern societies have to face. They represent incurable, progressive conditions with diverse and complex pathological features, followed by catastrophic occurrences of massive neuronal loss at the later stages of the diseases. Some of these disorders, like Huntington’s disease (HD), rely on defined genetic factors. HD, as an incurable, fatal hereditary neurodegenerative disorder characterized by its mid-life onset, is caused by the expansion of CAG trinucleotide repeats coding for glutamine (Q) in exon 1 of the huntingtin gene. Apart from the genetic defect, environmental factors are thought to influence the risk, onset and progression of HD. As epigenetic mechanisms are known to readily respond to environmental stimuli, they are proposed to play a key role in HD pathogenesis. Indeed, dynamic epigenomic remodeling is observed in HD patients and in brains of HD animal models. Epigenetic signatures, such as DNA methylation, histone variants and modifications, are known to influence gene expression and to orchestrate various aspects of neuronal physiology. Hence, deciphering their implication in HD pathogenesis might open up new paths for novel therapeutic concepts, which are discussed in this review.

In eukaryotes, DNA wraps around histones to form nucleosomes, which are compacted into chromatin. DNA-templated processes, including transcription, require chromatin disassembly and reassembly mediated by histone chaperones. Additionally, distinct histone variants can replace core histones to regulate chromatin structure and function. Although replacement of H2A with the evolutionarily conserved H2A.Z via the SWR1 histone chaperone complex has been extensively studied, in plants little is known about how a reduction of H2A.Z levels can be achieved. Here, we show that NRP proteins cause a decrease of H2A.Z-containing nucleosomes in Arabidopsis under standard growing conditions. nrp1-1 nrp2-2 double mutants show an over-accumulation of H2A.Z genome-wide, especially at heterochromatic regions normally H2A.Z-depleted in wild-type plants. Our work suggests that NRP proteins regulate gene expression by counteracting SWR1, thereby preventing excessive accumulation of H2A.Z., The histone variant H2A.Z is deposited by the SWR1 complex to replace H2A in Arabidopsis, but the mechanism of H2A.Z removal is unclear. Here, the authors show that NRP proteins can regulate gene expression by counteracting SWR1 and prevent excessive accumulation of H2A.Z.

Histone ubiquitination plays an important role in the DNA damage response (DDR) pathway. RNF168 catalyzes H2A and H2AX ubiquitination on lysine 13/15 (K13/K15) upon DNA damage and promotes the accrual of downstream repair factors at damaged chromatin. Here, we report that RNF168 ubiquitinates the non-canonical H2A variants H2AZ and macroH2A1/2 at the divergent N-terminal tail lysine residue. In addition to their evolutionarily conserved nucleosome acidic patch, we identify the positively charged alpha1-extension helix as essential for RNF168-mediated ubiquitination of H2A variants. Moreover, mutation of the RNF168 UMI (UIM- and MIU-related UBD) hydrophilic acidic residues abolishes RNF168-mediated ubiquitination as well as 53BP1 and BRCA1 ionizing radiation-induced foci formation. Our results reveal a juxtaposed bipartite electrostatic interaction utilized by the nucleosome to direct RNF168 orientation towards the target lysine residues in proximity to the H2A alpha1-extension helix, which plays an important role in the DDR pathway., Histone ubiquitination plays a critical role in the DNA damage response pathway. Here the authors reveal how RNF168 ubiquitinates the H2A family including noncanonical variants, H2AZ and macroH2A1/2, at the divergent N-terminal tail lysine residue.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience., Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.

Histone chaperones include a wide variety of proteins which associate with histones and regulate chromatin structure. The classic H2A–H2B type of histone chaperones, and the chromatin remodeling complex components possessing H2A–H2B chaperone activity, show a broad range of structures and functions. Rapid progress in the structural and functional study of H2A–H2B chaperones extends our knowledge about the epigenetic regulation of chromatin. In this review, we summarize the most recent advances in the understanding of the structure and function of H2A–H2B chaperones that interact with either canonical or variant H2A–H2B dimers. We discuss the current knowledge of the H2A–H2B chaperones, which present no preference for canonical and variant H2A–H2B dimers, describing how they interact with H2A–H2B to fulfill their functions. We also review recent advances of H2A variant-specific chaperones, demarcating how they achieve specific recognition for histone variant H2A.Z and how these interactions regulate chromatin structure by nucleosome editing. We highlight the universal mechanism underlying H2A–H2B dimers recognition by a large variety of histone chaperones. These findings will shed insight into the biological impacts of histone chaperone, chromatin remodeling complex, and histone variants in chromatin regulation.

Complex multi-cellular organisms are shaped starting from a single-celled zygote, owing to elaborate developmental programs. These programs involve several layers of regulation to orchestrate the establishment of progressively diverging cell type-specific gene expression patterns. In this scenario, epigenetic modifications of chromatin are central in influencing spatiotemporal patterns of gene transcription. In fact, it is generally recognized that epigenetic changes of chromatin states impact on the accessibility of genomic DNA to regulatory proteins. Several lines of evidence highlighted that zebrafish is an excellent vertebrate model for research purposes in the field of developmental epigenetics. In this review, I focus on the dynamic roles recently emerged for histone post-translational modifications (PTMs), histone modifying enzymes, histone variants and histone themselves in the coordination between the precise execution of transcriptional programs and developmental progression in zebrafish. In particular, I first outline a synopsis of the current state of knowledge in this field during early embryogenesis. Then, I present a survey of histone-based epigenetic mechanisms occurring throughout morphogenesis, with a stronger emphasis on cardiac formation. Undoubtedly, the issues addressed in this review take on particular importance in the emerging field of comparative biology of epigenetics, as well as in translational research.