Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome
ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association with chromatin.
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ABSTRACT: Each mammalian female cell transcriptionally inactivates one X chromosome to balance X-linked gene dosage between males and females. This phenomenon, called X chromosome inactivation, is a perfect epigenetic event, in which two chromosomes with identical DNA sequences are solely distinguished by epigenetic modifications. In this case, epigenetic marks, such as histone modifications, histone variants, DNA methylation, and ncRNAs, are all enriched on one chromosome, the inactive X chromosome (Xi), to establish its chromosome-wide gene silencing. At face value, it seems that the gene silencing mechanism of Xi is well understood. However, the "silence" of Xi in somatic cells is so tightly maintained that it remains largely intact even after almost all known epigenetic modifications are artificially depleted. To understand how the gene silence of Xi is maintained in soma is a major challenge in current research. We summarize the current knowledge related with this issue and discuss future research directions.genesis 11/2011; 49(11):821-34. DOI:10.1002/dvg.20792 · 2.04 Impact Factor
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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.Developmental Cell 11/2010; 19(5):662-74. DOI:10.1016/j.devcel.2010.10.014 · 10.37 Impact Factor
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ABSTRACT: MacroH2A1 is a histone variant that is enriched on the inactive X chromosome (Xi) in mammals and is postulated to play an important, but unknown, role in the repression of gene expression. Here we show that, although macroH2A1 marks repressed autosomal chromatin, it positively regulates transcription when located in the transcribed regions of a subset of its target genes. We used chromatin immunoprecipitation (ChIP) coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of macroH2A1 in IMR90 human primary lung fibroblasts and MCF-7 breast cancer cells. The patterns of macroH2A1 deposition are largely similar across the autosomes of both cell lines. Our studies revealed a genomic localization pattern unique among histone variants; namely, the occupation by macroH2A1 of large chromatin domains (>500 kb in some cases) that contain repressive chromatin marks (e.g., histone H3 Lys 27 trimethylation). The boundaries of macroH2A1-containing domains tend to occur in promoter-proximal regions. Not all promoters, however, serve as macroH2A1 boundaries; many macroH2A1-containing chromatin domains invade the transcribed regions of genes whose products play key roles in development and cell-cell signaling. Surprisingly, the expression of a subset of these genes is positively regulated by macroH2A1. MacroH2A1 also plays a role in augmenting signal-regulated transcription, specifically for genes responsive to serum starvation. Collectively, our results document an unexpected role for macroH2A1 in the escape from heterochromatin-associated silencing and the enhancement of autosomal gene transcription.Genes & development 12/2009; 24(1):21-32. DOI:10.1101/gad.1876110 · 12.64 Impact Factor