Modulation of histone H3 variant synthesis during the myoblast-myotube transition of chicken myogenesis

doi:10.1016/0012-1606(87)90210-7

Developmental Biology

Volume 119, Issue 1, January 1987, Pages 94-99

https://doi.org/10.1016/0012-1606(87)90210-7 Get rights and content

Abstract

We have previously reported that nucleosomal histones are synthesized by cultured, postmitotic myotube cells at 9–29% of the rate in their dividing myoblast precursors (A. M. Wunsch, A. L. Haas, and J. Lough, 1987, Dev. Biol., 119, 85–93). In that study, histones were separated by two-dimensional polyacrylamide gels containing 8 M urea in the first-dimension to optimally separate variants of the H2A class. To separate and compare synthesis of variants in the H2B and H3 classes during myogenesis, 5.75 M urea has been used in the first dimension. Although no changes in the H2B variant pattern were discerned, a dramatic change in H3 variant synthesis was detected, in which a predominance of H3.2 synthesis in dividing myoblasts was almost completely replaced by a lower level of H3.3 synthesis after myotube formation. With increasing differentiation, H3.2 synthesis became undetectable, while H3.3 synthesis continued. Control experiments indicated that these results were not mediated by replicating cells in the myotube cultures, the effects of cytosine arabinoside, or contaminating non-histone proteins. These results suggest that histone H3.2 is replaced by histone H3.3 in nucleosomes during skeletal muscle maturation.

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Rhabdomyomas are benign tumors with skeletal muscle differentiation that are broadly divided into cardiac and extracardiac types. The latter demonstrate a predilection for head and neck and genital locations and are further subclassified into adult-type rhabdomyoma (ATRM), fetal-type rhabdomyoma (FTRM) and genital rhabdomyoma (GRM). Most extracardiac rhabdomyomas that arise in paratesticular tissues have a somewhat distinctive morphology and have been termed sclerosing rhabdomyomas (SRM). Therefore, we hypothesized that these tumors may harbor recurrent genetic alterations. In this study, we assessed 15 paratesticular rhabdomyomas (11 initially classified as SRM, 2 cellular FTRM and 2 ATRM) using massively parallel DNA and RNA sequencing. Five of 14 successfully sequenced cases harbored a novel H3C2 p.K37I mutation (4 SRM and 1 ATRM). This mutation replaced a highly conserved lysine residue that is a target for epigenetic modifications and plays a role in regulation of DNA replication. Moreover, 4 tumors (2 cellular FTRM, 1 case initially diagnosed as SRM and 1 ATRM) had complex copy number profiles characterized by numerous chromosome-level and arm-level copy number gains, consistent with a ploidy shift. Rereview of the SRM with copy number gains demonstrated that it was significantly more cellular and had a more prominent fascicular architecture than the rest of the SRMs included in this series. Therefore, it was retrospectively reclassified as a cellular FTRM. In conclusion, this study demonstrated that paratesticular rhabdomyomas harbor recurrent somatic H3C2 p.K37I mutations and ploidy shifts.
Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements
2020, iScience
Citation Excerpt :
Polyadenylated canonical histone H3.1 mRNA could induce genomic instability and cell transformation by disrupting the balance between canonical and variant histones. Deposition of canonical histone H3.1 is coupled with DNA replication, and its expression is largely limited to the S phase of the cell cycle, whereas histone variant H3.3 is expressed throughout the cell cycle independent of DNA replication (Brown et al., 1985; Green et al., 2005; Tagami et al., 2004; Wu et al., 1982; Wunsch and Lough, 1987). Polyadenylated canonical H3.1 mRNAs following arsenic exposure were increased during S phase and were also presented outside of S phase (Brocato et al., 2014).
Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3′ end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cells in vitro. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein, resulting in displacement of histone variant H3.3 at active promoters, enhancers, and insulator regions, leading to transcriptional deregulation, G2/M cell-cycle arrest, chromosome aneuploidy, and aberrations. In support of these observations, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation. Notably, arsenic exposure also resulted in displacement of H3.3 from active promoters, enhancers, and insulator regions. These data suggest that H3.3 displacement might be central to carcinogenesis caused by polyadenylation of H3.1 mRNA upon arsenic exposure. Our findings illustrate the importance of proper histone stoichiometry in maintaining genome integrity.
Temporal regulation of chromatin during myoblast differentiation
2017, Seminars in Cell and Developmental Biology
Citation Excerpt :
Variants of three of the four core histones (H2A, H2B, H3) exist and play specialized roles in different biological processes. To date, there is no evidence for a role for H2B variants in myogenesis [42]. Replacement of canonical histones with histone variants of H2A and H3 contributes to the regulation of gene expression during skeletal muscle differentiation.
The commitment to and execution of differentiation programmes involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The MyoD family of closely related, lineage-determining transcription factors directs, largely through targeting to chromatin, a cascade of cooperating transcription factors and enzymes that incorporate or remove variant histones, post-translationally modify histones, and alter nucleosome structure and positioning via energy released by ATP hydrolysis. The coordinated action of these transcription factors and enzymes prevents expression of differentiation-specific genes in myoblasts and facilitates the transition of these genes from transcriptionally repressed to activated during the differentiation process. Regulation is achieved in both a temporal as well as spatial manner, as at least some of these factors and enzymes affect local chromatin structure at myogenic gene regulatory sequences as well as higher-order genome organization. Here we discuss the transition of genes that promote myoblast differentiation from the silenced to the activated state with an emphasis on the changes that occur to individual histones and the chromatin structure present at these loci.
Centromeric chromatin and the pathway that drives its propagation
2012, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Citation Excerpt :
New CENP-A protein is synthesized after S phase in G2 and deposited later during mitotic exit and following G1 in human cells and fruit fly embryos [39,80,82–84]. This cell cycle timing is distinct from the H3 variants found in bulk chromatin, H3.1 (canonical H3), H3.2, and H3.3 [85–88]. H3.1/H3.2 are both synthesized and deposited into chromatin during S phase [85,89,90], and associate with CAF-1 [91–94], a chromatin assembly factor that associates with PCNA [95], the sliding DNA clamp used during DNA synthesis [96].
The centromere is the locus that directs chromosomal inheritance at cell division. While centromeres in diverse eukaryotes are commonly found at sites of repetitive DNA, their location is epigenetically specified. The histone H3 variant CENP-A is the prime candidate for epigenetically marking the centromere, and recent work has uncovered several additional proteins that play key roles in centromere assembly and maintenance. We describe advances in the identification and characterization of proteins that form the centromere, and focus on recent findings that have advanced our understanding of the assembly of functional centromeric chromatin. This article is part of a Special Issue entitled: Histone chaperones and chromatin assembly.
Histone Variants in Metazoan Development
2010, Developmental Cell
Citation Excerpt :
Neurons in the mammalian central nervous system are postmitotic, and several lines of evidence suggest that macroH2A, H3.3, and H2AX are likely to play important roles in neuronal biology. h3.3A RNA and protein levels are observed to increase in multiple models of cell differentiation (Krimer et al., 1993; Lord et al., 1990; Wu et al., 1982; Wunsch and Lough, 1987). High levels of H3.3 protein have been found in differentiating rat neurons, and H3.3 has been shown to be the dominant H3 protein in rat cortical neurons (Bosch and Suau, 1995; Pina and Suau, 1987; Scaturro et al., 1995).
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.
Histone H3.1 and H3.3 Complexes Mediate Nucleosome Assembly Pathways Dependent or Independent of DNA Synthesis
2004, Cell
Deposition of the major histone H3 (H3.1) is coupled to DNA synthesis during DNA replication and possibly DNA repair, whereas histone variant H3.3 serves as the replacement variant for the DNA-synthesis-independent deposition pathway. To address how histones H3.1 and H3.3 are deposited into chromatin through distinct pathways, we have purified deposition machineries for these histones. The H3.1 and H3.3 complexes contain distinct histone chaperones, CAF-1 and HIRA, that we show are necessary to mediate DNA-synthesis-dependent and -independent nucleosome assembly, respectively. Notably, these complexes possess one molecule each of H3.1/H3.3 and H4, suggesting that histones H3 and H4 exist as dimeric units that are important intermediates in nucleosome formation. This finding provides new insights into possible mechanisms for maintenance of epigenetic information after chromatin duplication.

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^☆: This work was supported by NIH Grants AM 34679 and HD 20743.

²: A.M.W. was supported by a Predoctoral Fellowship from the American Heart Association, Wisconsin Affiliate.

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Developmental Biology

Abstract

References (25)

Isolation and purification of myotube and myoblast nuclei from cultures of embryonic chick skeletal muscle

Exp. Cell Res

The cyanogen bromide reaction

Re-examination of histone changes during development of newt embryos

Exp. Cell Res

Differentiation of creatine phosphokinase during myogenesis: Quantitative fractionation of isozymes

Dev. Biol

Change in a nuclear phosphoprotein during in vitro myogenesis

Exp. Cell Res

Histone subtypes and switches in synthesis of histone subtypes during Ilyanassa development

Dev. Biol

Isolation and characterization of nuclei and purification of chromatin from differentiating cultures of rat skeletal muscle

Exp. Cell Res

Specific alterations in the pattern of histone-3 synthesis during conversion of human leukemic cells to terminally differentiated cells in culture

Differentiation

Changes in nucleosomal core histone variants during chicken development and maturation

Dev. Biol

Separation of basal histone synthesis from S-phage histone synthesis in dividing cells

Cell

Patterns of histone variant synthesis can distinguish G₀ from G₁ cells

Cell

Synthesis and ubiquitination of histones during myogenesis

Dev. Biol

Cited by (32)

Molecular assessment of paratesticular rhabdomyomas demonstrates recurrent findings, including a novel H3C2 p.K37I mutation

Polyadenylation of Histone H3.1 mRNA Promotes Cell Transformation by Displacing H3.3 from Gene Regulatory Elements

Temporal regulation of chromatin during myoblast differentiation

Centromeric chromatin and the pathway that drives its propagation

Histone Variants in Metazoan Development

Histone H3.1 and H3.3 Complexes Mediate Nucleosome Assembly Pathways Dependent or Independent of DNA Synthesis

Full paperModulation of histone H3 variant synthesis during the myoblast-myotube transition of chicken myogenesis☆

Abstract

Exp. Cell Res

Exp. Cell Res

Dev. Biol

Exp. Cell Res

Dev. Biol

Exp. Cell Res

Differentiation

Dev. Biol

Cell

Cell

Dev. Biol

Full paper
Modulation of histone H3 variant synthesis during the myoblast-myotube transition of chicken myogenesis☆