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The role of epigenetic phenomena in cancer biology is increasingly being recognized. Here we focus on the mechanisms and enzymes involved in regulating histone methylation and acetylation, and the modulation of histone variant expression and deposition. Implications of these epigenetic marks for tumor development, progression and invasiveness are discussed with a particular emphasis on breast cancer progression. [ABSTRACT FROM AUTHOR]

Embryonic stem (ES) cells are pluripotent cells that can self renew or be induced to differentiate into multiple cell lineages, and thus have the potential to be utilized in regenerative medicine. Key pluripotency specific factors (Oct 4/Sox2/Nanog/Klf4) maintain the pluripotent state by activating expression of pluripotency specific genes and by inhibiting the expression of developmental regulators. Pluripotent ES cells are distinguished from differentiated cells by a specialized chromatin state that is required to epigenetically regulate the ES cell phenotype. Recent studies show that in addition to pluripotency specific factors, chromatin remodeling enzymes play an important role in regulating ES cell chromatin and the capacity to self-renew and to differentiate. Here we review recent studies that delineate the role of ATP dependent chromatin remodeling enzymes in regulating ES cell chromatin structure. [ABSTRACT FROM AUTHOR]

One of the most obscure phenomena in modern biology is the near genome-wide displacement of histones that occurs during the postmeiotic phases of spermatogenesis in many species. Here we review the literature to show that, during spermatogenic differentiation, three major molecular mechanisms come together to ‘prepare’ the nucleosomes for facilitated disassembly and histone removal. [ABSTRACT FROM AUTHOR]

Chromatin can be modified by posttranslational modifications of histones, ATP-dependent remodeling, and incorporation of histone variants. The Saccharomyces cerevisiae protein Yaf9 is a subunit of both the essential histone acetyltransferase complex NuA4 and the ATP-dependent chromatin remodeling complex SWR1-C, which deposits histone variant H2A.Z into euchromatin. Yaf9 contains a YEATS domain, found in proteins associated with multiple chromatin-modifying enzymes and transcription complexes across eukaryotes. Here, we established the conservation of YEATS domain function from yeast to human, and determined the structure of this region from Yaf9 by x-ray crystallography to 2.3 Å resolution. The Yaf9 YEATS domain consisted of a β-sandwich characteristic of the Ig fold and contained three distinct conserved structural features. The structure of the Yaf9 YEATS domain was highly similar to that of the histone chaperone Asf 1. a similarity that extended to an ability of Yaf9 to bind histones H3 and H4 in vitro. Using structure-function analysis, we found that the YEATS domain was required for Yaf9 function, histone variant H2A.Z chromatin deposition at specific promoters, and H2A.Z acetylation. [ABSTRACT FROM AUTHOR]

There has been a hotbed of activity surrounding MeCP2 research in the past number of years. Despite better characterizing the functions and nature of this protein, it has become abundantly clear that MeCP2 is involved in far more complex activities than perhaps initially anticipated. Recent publications have shown that MeCP2 is dynamically post-translationally modified, and it is possible that these marks permit MeCP2 to inhabit very diverse chromatin environments. It is also of interest to consider how nucleosome composition differs in these varying chromatin regions, and how the chromatin template itself contributes to diversifying the regulatory roles of MeCP2. These will be critical points to examine when seeking to understand how MeCP2 behaviour differentiates in tissues other than the brain. By understanding the chromatin and (or) tissue context in which MeCP2 interacts, it may be possible to discern the specific etiology of diseases linked to MeCP2 dysfunction. [ABSTRACT FROM AUTHOR]

Structural variability within histone families, such as H2A, can be achieved through 2 primary mechanisms: the expression of histone variants and the incorporation of chemical modifications. The histone H2A family contains several variants in addition to the canonical H2A forms. In this review, recent developments in the study of the heteromorphous variants H2A.X, H2A.Z, and macroH2A will be discussed. Particular focus will be given to the post-translational modifications (PTMs) of these variants, including phosphorylation, ubiquitination, acetylation, and methylation. The combination of the newly identified N- and C-terminal tail PTMs expands the multiplicity of roles that the individual H2A variants can perform. It is of additional interest that analogous sites within these different histone variants can be similarly modified. Whether this is a redundant function or a finely tuned one, designed to meet specific needs, remains to be elucidated. La variabilité de structure au sein des familles d’histones, comme la famille H2A, peut être obtenue grâce à deux mécanismes principaux : l’expression de variants d’histones et l’incorporation de modifications chimiques. La famille d’histones H2A comporte plusieurs variants en plus de la forme canonique H2A. Les derniers développements de l’étude des variants hétéromorphes H2A.X, H2A.Z et macroH2A seront discutés dans cet article de revue. Une attention particulière sera portée aux modifications post-traductionnelles (MPT) de ces variants, notamment la phosphorylation, l’ubiquitination, l’acétylation et la méthylation. La combinaison de ces modifications post-traductionnelles des extrémités N- et C-terminales nouvellement identifiées augmente la multiplicité des rôles que ces variants individuels de H2A peuvent jouer. Il est d’un intérêt supplémentaire de constater que les sites analogues au sein de ces différents variants d’histones puissent être similairement modifiés. Il reste à déterminer s’il s’agit d’une redondance de fonctions ou plutôt d’un contrôle fin conçu pour combler des besoins spécifiques. [ABSTRACT FROM AUTHOR]

Skeletal muscle development and regeneration rely on the successive activation of specific transcription factors that engage cellular fate, promote commitment, and drive differentiation. Emerging evidence demonstrates that epigenetic regulation of gene expression is crucial for the maintenance of the cell differentiation status upon division and, therefore, to preserve a specific cellular identity. This depends in part on the regulation of chromatin structure and its level of condensation. Chromatin architecture undergoes remodeling through changes in nucleosome composition, such as alterations in histone post-translational modifications or exchange in the type of histone variants. The mechanisms that link histone post-translational modifications and transcriptional regulation have been extensively evaluated in the context of cell fate and differentiation, whereas histone variants have attracted less attention in the field. In this review, we discuss the studies that have provided insights into the role of histone variants in the regulation of myogenic gene expression, myoblast differentiation, and maintenance of muscle cell identity. [ABSTRACT FROM AUTHOR]

Abstract: Histone H2A.Bbd (Barr body-deficient) is a novel histone variant which is largely excluded from the inactive X chromosome of mammals. Discovered only 6 years ago, H2A.Bbd displays very unusual structural and functional properties, for instance, it is relatively shorter and only 48% identical compared to H2A, lacking both the typical C-terminal tail of the H2A family and the very last sequence of the docking domain, making it the most specialized among all histone variants known to date. Indeed, molecular evolutionary analyses have shown that H2A.Bbd is a highly hypervariable and quickly evolving protein exclusive to mammalian lineages, in striking contrast to all other histones. Different studies have described a deposition pattern of H2A.Bbd in the chromatin that overlaps with regions of histone H4 acetylation suggesting its association with transcriptionally active euchromatic regions of the genome. In this regard, it is believed that this histone variant plays an important role in determining such regions by destabilizing the nucleosome and locally unfolding the chromatin fiber. This review provides a concise, comprehensive and timely summary of the work published on H2A.Bbd structure and function. Special emphasis is placed on its chromatin deposition patterns in relation to gene expression profiles and its evolutionary history, as well as on the dynamics of H2A.Bbd-containing nucleosomes. [Copyright &y& Elsevier]

Abstract: A protein–protein Förster resonance energy transfer (FRET) system, employing probes at multiple positions, was designed to specifically monitor the dissociation of the H2A–H2B dimer from the nucleosome core particle (NCP). Tryptophan donors and Cys-AEDANS acceptors were chosen because, compared to previous NCP FRET fluorophores, they: (1) are smaller and less hydrophobic, which should minimize perturbations of histone and NCP structure; and (2) have an R 0 of 20 Å, which is much less than the dimensions of the NCP (∼50 Å width and ∼100 Å diameter). Equilibrium protein unfolding titrations indicate that the donor and acceptor moieties have minimal effects on the stability of the H2A–H2B dimer and (H3–H4)2 tetramer. NCPs containing the various FRET pairs were reconstituted with the 601 DNA positioning element. Equilibrium NaCl-induced dissociation of the modified NCPs showed that the 601 sequence stabilized the NCP to dimer dissociation relative to weaker positioning sequences. This finding implies a significant role for the H2A–H2B dimers in determining the DNA sequence dependence of NCP stability. The free energy of dissociation determined from reversible and well-defined sigmoidal transitions revealed two distinct phases reflecting the dissociation of individual H2A–H2B dimers, confirming cooperativity as suggested previously; these data allow quantitative description of the cooperativity. The FRET system was then used to study the effects of the histone variant H2A.Z on NCP stability; previous studies have reported both destabilizing and stabilizing effects. H2A.Z FRET NCP dissociation transitions suggest a slight increase in stability but a significant increase in cooperativity of the dimer dissociations. Thus, the utility of this protein–protein FRET system to monitor the effects of histone variants on NCP dynamics has been demonstrated, and the system appears equally well-suited for dissection of the kinetic processes of dimer association and dissociation from the NCP. [Copyright &y& Elsevier]

Abstract: Histone variants replace the core histones in a substantial fraction of nucleosomes, affecting chromatin structure and impacting chromatin-templated processes. In many instances incorporation of histone variants results in formation of specialized regions of chromatin. Proper localization of histone variants to distinct regions of the genome is critical for their function, yet how this specific localization is achieved remains unclear. macroH2A1 is enriched on the inactive X chromosome in female mammalian cells, where it functions to maintain gene silencing. macroH2A1 consists of a histone H2A-like histone domain and a large, globular C-terminal macro domain that is not present in other histone proteins. The histone domain of macroH2A1 is alone sufficient to direct enrichment on the inactive X chromosome when expressed in female cells, indicating that sequences important for correct localization lie in this domain. Here we investigate whether divergent sequences of the H2A variant macroH2A1 contribute to its correct localization. We mapped the regions of the macroH2A1 histone domain that are sufficient for localization to the inactive X chromosome using chimeras between H2A and the histone domain of macroH2A1. Multiple short sequences dispersed along the macroH2A1 histone domain individually supported enrichment on the inactive X chromosome when introduced into H2A. These sequences map to the surface of the macroH2A1/H2B dimer, but are buried in the crystal structure of the macroH2A1 containing nucleosome, suggesting that they may contribute to recognition by macroH2A1/H2B deposition factors. [Copyright &y& Elsevier]

Abstract: Compartmentalization and compaction of DNA in the nucleus is the characteristic feature of eukaryotic cells. A fully extended DNA molecule has to be compacted 100,000 times to fit within the nucleus. At the same time it is critical that various DNA regions remain accessible for interaction with regulatory factors and transcription/replication factories. This puzzle is solved at the level of DNA packaging in chromatin that occurs in several steps: rolling of DNA onto nucleosomes, compaction of nucleosome fiber with formation of the so-called 30 nm fiber, and folding of the latter into the giant (50–200 kbp) loops, fixed onto the protein skeleton, the nuclear matrix. The general assumption is that DNA folding in the cell nucleus cannot be uniform. It has been known for a long time that a transcriptionally active chromatin fraction is more sensitive to nucleases; this was interpreted as evidence for the less tight compaction of this fraction. In this review we summarize the latest results on structure of transcriptionally active chromatin and the mechanisms of transcriptional regulation in the context of chromatin dynamics. In particular the significance of histone modifications and the mechanisms controlling dynamics of chromatin domains are discussed as well as the significance of spatial organization of the genome for functioning of distant regulatory elements. [Copyright &y& Elsevier]

Recent years are marked by a notable increase in interest in the role of chromatin in the regulation of gene activity. In the 1970s, numerous studies were undertaken in order to identify different forms of histones involved in selective transcription activation. The results of these studies were conflicting. Determination of the primary structures of major histone forms demonstrated their extreme conservation. Nucleosome particles, constructed from histones, were considered conserved as well. Later, this concept changed. Many noncanonical forms (variants) of nucleosomal core histones encoded by separate genes were discovered. It was shown that both canonical forms and variants of histones could experience different posttranslational modifications. Thus, many different nucleosome particles can be assembled. Furthermore, a clear correlation between certain modifications of histones and DNA packaging in either active or inactive chromatin was established in recent years. Similarly, the formation of active (inactive) chromatin correlates with the incorporation of particular histone variants into nucleosomes. The hypothesis of a histone code was proposed, assuming that signals exposed on the nucleosome surface are important for regulation of chromatin domain activity. The review considers the current views of the chromatin organization and its role in transcription regulation in higher eukaryotes. [ABSTRACT FROM AUTHOR]

Mammalian centromere function depends upon a specialized chromatin organization where distinct domains of CENP-A and dimethyl K4 histone H3, forming centric chromatin, are uniquely positioned on or near the surface of the chromosome. These distinct domains are embedded in pericentric heterochromatin (characterized by H3 methylated at Kg). The mechanisms that underpin this complex spatial organization are unknown. Here, we identify the essential histone variant H2A.Z as a new structural component of the centromere. Along linear chromatin fibers H2A.Z is distributed nonuniformly throughout heterochromatin, and centric chromatin where regions of nucleosomes containing H2A.Z and dimethylated K4 H3 are interspersed between subdomains of CENP-A. At metaphase, using the inactive X chromosome centromere as a model, complex folding of this fiber produces spatially positioned domains where H2A.Z/dimethylated K4 H3 chromatin juxtaposes one side of CENP-A chromatin, whereas a region of H2A/trimethyl K9 H3 borders the other side. A second region of H2A.Z is found, with trimethyl K9 H3 at the inner centromere. We therefore propose that H2A.Z plays an integral role in organizing centromere structure. [ABSTRACT FROM AUTHOR]

Transcriptional activation of the interleukin-8 (IL-8) gene is restricted to distinct cell types, although the transcriptional regulatory proteins controlling IL-8 gene expression are ubiquitous. We show that cell-specific transcription of IL-8 is due to the distinct chromatin architecture on the enhancer/promoter before the arrival of the inducing signal. In expressing epithelial cells the enhancer/promoter is nucleosome-free, whereas in non-expressing B cells a nucleosome masks the entire regulatory region. The B-cell-specific nucleosome contains the histone variant macroH2A, which is responsible for preventing transcription factor binding. Recruitment of the repressive macroH2A nucleosome requires direct interactions between ATF-2 bound to the nearby AP1 site and macroH2A and it is regulated by DNA-induced protein allostery. siRNA against ATF-2 or macroH2A rescues IL-8 transcription in B cells. Thus, a transcription factor can work as a transcriptional repressor by orchestrating and maintaining the assembly of specialized local chromatin architectures. [ABSTRACT FROM AUTHOR]

Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing number of mammalian histone variants, their particular biological functions and unique features, and how they may affect the structure of the nucleosome. We propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that we refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance. [ABSTRACT FROM AUTHOR]

Abstract: Histone macroH2A1.2 (macroH2A) is an unusual histone H2A variant with a large non-histone macrodomain at its carboxyl terminal. MacroH2A1.2 is enriched in facultative heterochromatin, including inactivated X chromosomes in mammalian females and senescence-associated heterochromatin foci. We show here that a small population of macroH2A1.2 is mono-ubiquitinated in human HeLa cells. Mass spectrometry analysis revealed that the specific targeting sites for the mono-ubiquitination are Lys115 and Lys116 of the histone domain. A corresponding Lys119 conserved in histone H2A is also mono-ubiquitinated by Ring protein in the polycomb group complex. We suggest that the mono-ubiquitination of macroH2A1.2 and histone H2A has similar or synergistic implications, but that the multiple ubiquitination sites in macroH2A1.2 might confer a variety of functions upon macroH2A1.2 to modulate chromatin states. [Copyright &y& Elsevier]

Recent research suggests that minor changes in the primary sequence of the conserved histones may become major determinants for the chromatin structure regulating gene expression and other DNA-related processes . An analysis of the involvement of different core histone variants in different nuclear processes and the structure of different variant nucleosome cores shows that this may indeed be so. Histone variants may also be involved in demarcating functional regions of the chromatin. We discuss in this review why two of the four core histones show higher variation. A comparison of the status of variants in yeast with those from higher eukaryotes suggests that histone variants have evolved in synchrony with functional requirement of the cell. [ABSTRACT FROM AUTHOR]

Deposition of variant histones provides a mechanism to reset and to potentially specify chromatin states. We determined the distribution of H3 and its variant H3.3 relative to chromatin structure and elongating polymerase. H3.3 is enriched throughout active genes similar to polymerase, yet its distribution is very distinct from that of several euchromatic histone modifications, which are highly biased toward the 5′ part of active genes. Upon gene induction we observe displacement of both H3 and H3.3 followed by selective deposition of H3.3. These results support a model in which H3.3 deposition compensates for transcription-coupled nucleosomal displacement yet does not predetermine tail modifications. [ABSTRACT FROM AUTHOR]

Replication of genomic material is a process that requires not only high fidelity in the duplication of DNA sequences but also inheritance of the chromatin states. In the last few years enormous effort has been put into elucidating the mechanisms involved in the correct propagation of chromatin states. From all these studies it emerges that an epigenetic network is at the base of this process. A coordinated interplay between histone modifications and histone variants, DNA methylation, RNA components, ATP-dependent chromatin remodeling, and histone-specific assembly factors regulates establishment of the replication timing program, initiation of replication, and propagation of chromatin domains. The aim of this review is to examine, in light of recent findings, how so many players can be coordinated with each other to achieve the same goal, a correct inheritance of the chromatin state. [ABSTRACT FROM AUTHOR]

In this review, we briefly analyze the current state of knowledge on histone variants and their posttranslational modifications. We place special emphasis on the description of the structural component(s) defining and determining their functional role. The information available indicates that this histone "variability" may operate at different levels: short-range "local" or long-range "global", with different functional implications. Recent work on this topic emphasizes an earlier notion that suggests that, in many instances, the functional response to histone variability is possibly the result of a synergistic structural effect.Key words: histone variants, posttranslational modifications, chromatin.Dans cette revue, nous analysons brièvement l'état actuel de nos connaissances concernant les variantes des histones et leurs modifications post-traductionnelles. Nous mettons particulièrement l'emphase sur la description des éléments structuraux définissant et déterminant leur rôle fonctionnel. L'information disponible montre que cette variabilité des histones peut avoir des effets à courte portée « locaux » ou à longue portée « globaux », avec différentes conséquences fonctionnelles. Un travail récent sur ce sujet met l'emphase sur un ancien concept suggérant que, dans plusieurs cas, la réponse fonctionnelle à la variabilité des histones résulterait d'un effet structural synergique.Mots clés : variants des histones, modifications post-traductionnelles, chromatine.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]

The contribution of the linker region to maintenance of condensed chromatin was examined in two model systems, namely sea urchin sperm nuclei and chicken red blood cell nuclei. Linkerless nuclei, prepared by extensive digestion with micrococcal nuclease, were compared with Native nuclei using several assays, including microscopic appearance, nuclear turbidity, salt stability, and trypsin resistance. Chromatin in the Linkerless nuclei was highly condensed, resembling pyknotic chromatin in apoptotic cells. Linkerless nuclei were more stable in low ionic strength buffers and more resistant to trypsin than Native nuclei. Analysis of histones from the trypsinized nuclei by polyacrylamide gel electrophoresis showed that specific histone H1, H2B, and H3 tail regions stabilized linker DNA in condensed nuclei. Thermal denaturation of soluble chromatin preparations from differentially trypsinized sperm nuclei demonstrated that the N-terminal regions of histones Sp H1, Sp H2B, and H3 bind tightly to linker DNA, causing it to denature at a high temperature. We conclude that linker DNA exerts a disruptive force on condensed chromatin structure which is counteracted by binding of specific histone tail regions to the linker DNA. The inherent instability of the linker region may be significant in all eukaryotic chromatins and may promote gene activation in living cells.Key words: chromatin condensation, sea urchin sperm, chicken red blood cell, nuclei, linker DNA, histone variants, micrococcal nuclease, nucleosome, trypsin, gel electrophoresis.La contribution de la région internucléosomique au maintien de la chromatine condensée a été étudiée dans deux systèmes modèles : les noyaux de spermatocytes d'oursin et les noyaux d'érythrocytes de poulet. Plusieurs paramètres de noyaux sans régions internucléosomiques, obtenus à la suite d'une digestion poussée par la nucléase micrococcique, telles l'apparence au microscope, la turbidité nucléaire, la stabilité en présence d'un sel et la résistance à la trypsine, ont été comparés à ceux de noyaux non traités. La chromatine des noyaux sans régions internucléosomiques est fortement condensée et ressemble à la chromatine pycnotique des cellules en apoptose. Les noyaux sans régions internucléosomiques sont plus stables dans les tampons à faible force ionique et plus résistants à la trypsine que les noyaux non traités. L'analyse des histones de noyaux incubés en présence de trypsine, par électrophorèse en gel de polyacrylamide, montre que les régions terminales spécifiques des histones H1, H2B et H3 stabilisent l'ADN internucléosomique dans les noyaux condensés. La dénaturation thermique de la chromatine soluble de noyaux de spermatocytes incubés pendant différentes périodes de temps en présence de trypsine démontre que les régions N-terminales spécifiques des histones H1, H2B et H3 de spermatocytes se lient fortement à l'ADN internucléosomique, de sorte que la chromatine se dénature seulement à température élevée. Nous concluons que l'ADN internucléosomique exerce une force de déstabilisation sur la structure de la chromatine condensée qui est contrecarrée par la liaison des régions terminales spécifiques des histones à l'ADN internucléosomique. L'instabilité inhérente de la région internucléosomique pourrait être importante dans la chromatine de tous les eucaryotes et pourrait entraîner l'activation de gènes dans les cellules vivantes.Mots clés : condensation de la chromatine, spermatocytes d'oursin, érythrocytes de poulet, noyaux, ADN internucléosomique, variantes des histones, nucléase micrococcique, nucléosome, trypsine, électrophorèse en gel.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]

Histone variants illuminate the behavior of chromatin through their unique structures and patterns of postsynthetic modification. This review examines the literature on heteromorphous histone structures in chromatin, structures that are primary targets for histone kinases and phosphatases in vivo. Special attention is paid to certain well-studied experimental systems: mammalian culture cells, chicken erythrocytes, sea urchin sperm, wheat sprouts, Tetrahymena, and budding yeast. A common theme emerges from these studies. Specialized, highly basic structures in histone variants promote chromatin condensation in a variety of developmental situations. Before, and sometimes after condensed chromatin is formed, the chromatin is rendered soluble by phosphorylation of the heteromorphous regions, preventing their interaction with linker DNA. A simple structural model accounting for histone variation and phosphorylation is presented.Key words: phosphorylation, histone variants, chromatin, linker DNA.La structure et le patron de modification post-traductionnelle uniques des variantes des histones permettent de mieux comprendre le comportement de la chromatine. Cette revue de la littérature porte sur les structures hétéromorphes des histones de la chromatine, ces structures étant les principales cibles des kinases et des phosphatases des histones in vivo. Une attention particulière est portée à des systèmes expérimentaux bien étudiés : cellules de mammifères en culture, érythrocytes de poulet, sperme d'oursin, germe de blé, Tetrahymena et levure en bourgeonnement. Un thème commun émerge de ces études : les structures spécialisées très basiques des variantes des histones favorisent la condensation de la chromatine dans diverses situations de développement. Avant et parfois après que la chromatine se soit condensée, la chromatine est solubilisée à la suite de la phosphorylation des régions hétéromorphes, ce qui les empêche d'interagir avec l'ADN internucléosomique. Un modèle structural simple rendant compte de la variation et de la phosphorylation des histones est présenté.Mots clés : phosphorylation, variantes, histones, chromatine, ADN internucléosomique.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]

The family of human histone genes consists of replication-dependent and independent subtypes. The replication-independent histone genes, also known as variants, give rise to distinct mRNAs, whose expression is regulated depending on the growth state of the cell, tissue type and developmental stage. In turn, the histone variants are differentially synthesized and modified by acetylation. Consequently, chromatin structure is altered resulting in complex changes in gene expression. The high conservation among histone protein subtypes suggests that they are indispensable. In addition, conservation of the positions of acetylation within subtypes suggests that the location of these sites is functionally important for the eukaryotic cell. For example, the structures of transcriptionally active and repressed chromatin are different depending on the acetylation state of histone proteins [1–3]. In addition, transcriptionally active and repressed chromatin contains distinct histone variants [4]. Specialized histone variants are targeted to the centromere of the chromosome, where they are essential for chromosome segregation [5]. Other specialized histones exist that are essential for development [6]. Changes in histone acetylation have been implicated in the down-regulation of a tumour suppressor gene in human breast cancer [7]. Acetylation also plays an important role in X chromosome inactivation as well as hormone-mediated transcriptional regulation [8, 9]. We propose here a novel model for histone variant gene regulation at the post-transcriptional level, which provides the groundwork to define the pathways regulating the synthesis of these variants. [ABSTRACT FROM AUTHOR]

Temperature is a key factor in determining plant growth and development, geographical distribution, and seasonal behavior. Plants accurately sense subtle changes in ambient temperature and alter their growth and development accordingly to improve their chances of survival and successful propagation. Thermomorphogenesis encompasses a variety of morphological changes that help plants acclimate to warm environmental temperatures. Revealing the molecular mechanism of thermomorphogenesis is important for breeding thermo-tolerant crops and ensuring food security under global climate change. Plant adaptation to elevated ambient temperature is regulated by multiple signaling pathways and epigenetic mechanisms such as histone modifications, histone variants, and non-coding RNAs. In this review, we summarize recent advances in the mechanism of epigenetic regulation during thermomorphogenesis with a focus on the model plant Arabidopsis thaliana and briefly discuss future prospects for this field., Competing Interests: Conflict of interestAll the authors declare no conflict of interest., (© The Author(s) 2022.)

H2A.Z is a histone variant that provides specific structural and docking-side properties to the nucleosome, resulting in diverse and specialised molecular and cellular functions. In this review, we discuss the latest studies uncovering new functional aspects of mammalian H2A.Z in gene transcription, including pausing and elongation of RNA polymerase II (RNAPII) and enhancer activity; DNA repair; DNA replication; and 3D chromatin structure. We also review the recently described role of H2A.Z in embryonic development, cell differentiation, neurodevelopment, and brain function. In conclusion, our cumulative knowledge of H2A.Z over the past 40 years, in combination with the implementation of novel molecular technologies, is unravelling an unexpected and complex role of histone variants in gene regulation and disease., Competing Interests: Declaration of interests All the authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Histone variants are crucial regulators of chromatin structure and gene transcription, yet their functions within the brain remain largely unexplored. Here, we show that the H2A histone variant H2A.Z is essential for neuronal survival. Mice lacking H2A.Z in GABAergic neurons or Purkinje cells (PCs) present with a progressive cerebellar ataxia accompanied by widespread degeneration of PCs. Ablation of H2A.Z in other neuronal subtypes also triggers cell death. H2A.Z binds to the promoters of key nuclear-encoded mitochondrial genes to regulate their expression and promote organelle function. Bolstering mitochondrial activity genetically or by organelle transplant enhances the survival of H2A.Z-ablated neurons. Changes in bioenergetic status alter H2A.Z occupancy at the promoters of nuclear-encoded mitochondrial genes, an adaptive response essential for cell survival. Our results highlight that H2A.Z fulfills a key, conserved role in neuronal survival by acting as a transcriptional rheostat to regulate the expression of genes critical to mitochondrial function. [Display omitted] • H2A.Z ablation in Purkinje cells leads to a progressive cerebellar ataxia in mice • H2A.Z promotes nuclear-encoded mitochondrial gene expression and organelle function • Neuronal cell death in the absence of H2A.Z is due to mitochondrial dysfunction • H2A.Z promotes organelle function in neuronal and non-neuronal cells Lowden et al. show that the histone variant H2A.Z has an essential role in neuronal survival by promoting the expression of nuclear-encoded mitochondrial genes and supporting organelle function. H2A.Z deficiency in Purkinje cells leads to Purkinje cell degeneration and progressive cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Histones and their posttranslational modifications facilitate diverse chromatin functions in eukaryotes. Core histones (H2A, H2B, H3, and H4) package genomes after DNA replication. In contrast, variant histones promote specialized chromatin functions, including DNA repair, genome stability, and epigenetic inheritance. Previous studies have identified only a few H2B variants in animals; their roles and evolutionary origins remain largely unknown. Here, using phylogenomic analyses, we reveal the presence of five H2B variants broadly present in mammalian genomes. Three of these variants have been previously described: H2B.1, H2B.L (also called subH2B), and H2B.W. In addition, we identify and describe two new variants: H2B.K and H2B.N. Four of these variants originated in mammals, whereas H2B.K arose prior to the last common ancestor of bony vertebrates. We find that though H2B variants are subject to high gene turnover, most are broadly retained in mammals, including humans. Despite an overall signature of purifying selection, H2B variants evolve more rapidly than core H2B with considerable divergence in sequence and length. All five H2B variants are expressed in the germline. H2B.K and H2B.N are predominantly expressed in oocytes, an atypical expression site for mammalian histone variants. Our findings suggest that H2B variants likely encode potentially redundant but vital functions via unusual chromatin packaging or nonchromatin functions in mammalian germline cells. Our discovery of novel histone variants highlights the advantages of comprehensive phylogenomic analyses and provides unique opportunities to study how innovations in chromatin function evolve., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Canonical histone H3.1 and variant H3.3 deposit at different sites of the chromatin via distinct histone chaperones. Histone H3.1 relies on chaperone CAF-1 to mediate replication-dependent nucleosome assembly during S-phase, while H3.3 variant is regulated and incorporated into the chromatin in a replication-independent manner through HIRA and DAXX/ATRX. Current literature suggests that dysregulated expression of histone chaperones may be implicated in tumor progression. Notably, ectopic expression of CAF-1 can promote a switch between canonical H3.1 and H3 variants in the chromatin, impair the chromatic state, lead to chromosome instability, and impact gene transcription, potentially contributing to carcinogenesis. This review focuses on the chaperone proteins of H3.1 and H3.3, including structure, regulation, as well as their oncogenic and tumor suppressive functions in tumorigenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wen and Chen.)