The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing

Matthew J. Gamble, Kristine M. Frizzell, Christine Yang, Raga Krishnakumar, W. Lee Kraus

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)21-32
Number of pages12
JournalGenes and Development
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Gene Silencing
Histones
Chromatin
Chromatin Immunoprecipitation
Genes
Heterochromatin
X Chromosome
Starvation
Occupations
Genetic Promoter Regions
Mammals
Fibroblasts
Breast Neoplasms
Gene Expression
Cell Line
Lung
Serum

Keywords

  • ChIP-chip
  • Histone variant
  • MacroH2A1
  • Transcription

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. / Gamble, Matthew J.; Frizzell, Kristine M.; Yang, Christine; Krishnakumar, Raga; Kraus, W. Lee.

In: Genes and Development, Vol. 24, No. 1, 01.01.2010, p. 21-32.

Research output: Contribution to journalArticle

Gamble, Matthew J. ; Frizzell, Kristine M. ; Yang, Christine ; Krishnakumar, Raga ; Kraus, W. Lee. / The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. In: Genes and Development. 2010 ; Vol. 24, No. 1. pp. 21-32.
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