The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing
The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing
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DOI：
10.1101/gad.1876110
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发表时间：
2010-01-01
影响因子：
10.5
通讯作者：
Kraus, W. Lee
中科院分区：
文献类型：
--
作者：
Gamble, Matthew J.;Frizzell, Kristine M.;Kraus, W. Lee
MacroH2A1 是一种组蛋白变体，在哺乳动物的失活 X 染色体 (Xi) 上富集，推测在基因表达抑制中发挥着重要但未知的作用。在这里，我们发现，虽然 MacroH2A1 标记了抑制的常染色体染色质，但当它位于其靶基因子集的转录区域时，它会正向调节转录。我们使用染色质免疫沉淀 (ChIP) 与平铺微阵列 (ChIP-chip) 相结合来确定 MacroH2A1 在 IMR90 人原代肺成纤维细胞和 MCF-7 乳腺癌细胞中的基因组定位。两种细胞系常染色体上的 MacroH2A1 沉积模式非常相似。我们的研究揭示了组蛋白变体中独特的基因组定位模式；即，macroH2A1 占据包含抑制性染色质标记（例如组蛋白 H3 Lys 27 三甲基化）的大染色质结构域（在某些情况下 >500 kb）。含有macroH2A1的结构域的边界往往出现在启动子近端区域。然而，并非所有启动子都充当 MacroH2A1 边界；许多含有 MacroH2A1 的染色质结构域侵入基因的转录区域，其产物在发育和细胞信号传导中发挥关键作用。令人惊讶的是，这些基因的一部分的表达受到 MacroH2A1 的正向调节。 MacroH2A1 还在增强信号调节转录方面发挥作用，特别是对血清饥饿反应的基因。总的来说，我们的结果证明了 MacroH2A1 在逃避异染色质相关沉默和增强常染色体基因转录方面发挥着意想不到的作用。
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.