Histone Variants in Metazoan Development

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Developmental Cell (Impact Factor: 10.37). 11/2010; 19(5):662-74. DOI: 10.1016/j.devcel.2010.10.014
Source: PubMed

ABSTRACT Embryonic development is regulated by both genetic and epigenetic mechanisms, with nearly all DNA-templated processes influenced by chromatin architecture. Sequence variations in histone proteins, core components of chromatin, provide a means to generate diversity in the chromatin structure, resulting in distinct and profound biological outcomes in the developing embryo. Emerging literature suggests that epigenetic contributions from histone variants play key roles in a number of developmental processes such as the initiation and maintenance of pericentric heterochromatin, X-inactivation, and germ cell differentiation. Here, we review the role of histone variants in the embryo with particular emphasis on early mammalian development.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone isoforms and their post-translational modifications (PTMs) play an important role in the control of many chromatin-related processes including transcription and DNA damage. Variants of histones H2A and H3 have been studied in depth and have been found to have distinct functions. Although 13 somatic histone H2B isoforms have been identified by various biochemical and mass spectrometric (MS) approaches, the distinct roles of these isoforms within human cells are as yet unknown. Here, we have developed quantitative MS techniques to characterize isoform-specific H2B expression across the cell cycle, in differentiated myogenic cells, and in different cancer cell lines to illuminate potential functional roles. Using the MS strategies that we developed, we identified differences in H2B isoform levels between different cancer cell types, suggesting cancer or tissue-specific H2B isoform regulation. In particular, we found large variations in the levels of isoforms H2B1B and H2B1M across the panel of cell lines. We also found that, while individual H2B isoforms do not differ in their acetylation levels, trends in the acetylation on all H2B isoforms correlated with acetylation on other histone family members in the cancer cell line panel. We also used the MS strategies to study H2B protein expression across the cell cycle and determined that H2B isoforms that are alternatively spliced to carry a polyadenylation signal rather than the standard histone downstream element are expressed independently of the cell cycle. However, the level of protein produced from the polyadenylated transcripts does not contribute significantly to the total pool of H2B isoforms translated across the cell cycle or in non-cycling myogenic cells. Our results show that H2B isoforms are expressed at varying levels in different cells, suggesting isoform-specific, and possibly cell-type-specific, H2B gene regulation. The bottom-up mass spectrometry technique we developed for H2B quantification is compatible with the current standard histone H3 and H4 bottom-up 'one-pot' analysis platform so that H2B isoforms and their modifications can be studied in future experiments at the same time as histone H3 and H4 modifications. Therefore, we have expanded the histone landscape that can be interrogated in future experiments.
    Epigenetics & Chromatin 04/2015; 8(1):15. DOI:10.1186/s13072-015-0006-8 · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many biological processes depend on very few copies of intervening elements, which makes such processes particularly susceptible to the stochastic fluctuations of these elements. The intrinsic stochasticity of certain processes is propagated across bio-logical levels, causing genotype-and environment-independent biological variation which might permit populations to better cope with variable environments. Biolog-ical variations of stochastic nature might also allow the accumulation of variations at the genetic level that are hidden from natural selection, which might have a great potential for population diversification. The study of any mechanism that resulted in the modulation of stochastic variation is, therefore, of potentially wide interest. I propose that sex might be an important modulator of the stochastic variation in gene expression, i.e., gene expression noise. Based on known associations between diVerent patterns of gene expression variation, I hypothesize that in metazoans the gene expression noise might be generally larger in heterogametic than in homoga-metic individuals. I directly tested this hypothesis by comparing putative genotype-and environment-independent variations in gene expression between females and males of Drosophila melanogaster strains. Also, considering the potential eVect of the propagation of gene expression noise across biological levels, I indirectly tested the existence of a metazoan sexual dimorphism in gene expression noise by analyzing putative genotype-and environment-independent variation in phenotypes related to interaction with the environment in D. melanogaster strains and metazoan species. The results of these analyses are consistent with the hypothesis that gene expression is generally noisier in heterogametic than in homogametic individuals. Further analyses and discussion of existing literature permits the speculation that the sexual dimorphism in gene expression noise is ultimately based on the nuclear dynamics in gametogenesis and very early embryogenesis of sex-specific chromosomes, i.e., Y and W chromosomes.
    01/2015; 3. DOI:10.7717/peerj.750
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A striking proportion of human cleavage-stage embryos exhibit chromosome instability (CIN). Notably, until now, no experimental model has been described to determine the origin and mechanisms of complex chromosomal rearrangements. Here, we examined mouse embryos deficient for the chromatin remodeling protein ATRX to determine the cellular mechanisms activated in response to CIN. We demonstrate that ATRX is required for silencing of major satellite transcripts in the maternal genome, where it confers epigenetic asymmetry to pericentric heterochromatin during the transition to the first mitosis. This stage is also characterized by a striking kinetochore size asymmetry established by differences in CENP-C protein between the parental genomes. Loss of ATRX results in increased centromeric mitotic recombination, a high frequency of sister chromatid exchanges and double strand DNA breaks, indicating the formation of mitotic recombination break points. ATRX-deficient embryos exhibit a twofold increase in transcripts for aurora kinase B, the centromeric cohesin ESCO2, DNMT1, the ubiquitin-ligase (DZIP3) and the histone methyl transferase (EHMT1). Thus, loss of ATRX activates a pathway that integrates epigenetic modifications and DNA repair in response to chromosome breaks. These results reveal the cellular response of the cleavage-stage embryo to CIN and uncover a mechanism by which centromeric fission induces the formation of large-scale chromosomal rearrangements. Our results have important implications to determine the epigenetic origins of CIN that lead to congenital birth defects and early pregnancy loss, as well as the mechanisms involved in the oocyte to embryo transition.

Full-text (2 Sources)

Available from
Sep 14, 2014