Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Genes Dev. 2011 May 1;25(9):959-71. doi: 10.1101/gad.2030811.
Chromosome-wide inactivation is an epigenetic signature of sex chromosomes. The mechanism by which the chromosome-wide domain is recognized and gene silencing is induced remains unclear. Here we identify an essential mechanism underlying the recognition of the chromosome-wide domain in the male germline. We show that mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (γH2AX), defines the chromosome-wide domain, initiates meiotic sex chromosome inactivation (MSCI), and leads to XY body formation. Importantly, MSCI consists of two genetically separable steps. The first step is the MDC1-independent recognition of the unsynapsed axis by DNA damage response (DDR) factors such as ataxia telangiectasia and Rad3-related (ATR), TOPBP1, and γH2AX. The second step is the MDC1-dependent chromosome-wide spreading of DDR factors to the entire chromatin. Furthermore, we demonstrate that, in somatic cells, MDC1-dependent amplification of the γH2AX signal occurs following replicative stress and is associated with transcriptional silencing. We propose that a common DDR pathway underlies both MSCI and the response of somatic cells to replicative stress. These results establish that the DDR pathway centered on MDC1 triggers epigenetic silencing of sex chromosomes in germ cells.
染色体-wide 失活是性染色体的一种表观遗传特征。染色体-wide 区域被识别以及基因沉默被诱导的机制仍不清楚。在这里，我们确定了雄性生殖细胞中识别染色体-wide 区域的基本机制。我们表明，DNA 损伤检查点 1 （MDC1），一种磷酸化组蛋白 H2AX（γH2AX）的结合伴侣，定义了染色体-wide 区域，启动了减数分裂性染色体失活（MSCI），并导致 XY 体形成。重要的是，MSCI 由两个在遗传上可分离的步骤组成。第一步是非 MDC1 依赖的通过 DNA 损伤反应（DDR）因子如共济失调毛细血管扩张症和 Rad3 相关（ATR）、TOPBP1 和 γH2AX 识别未配对轴。第二步是 MDC1 依赖性 DDR 因子向整个染色质的染色体-wide 扩散。此外，我们证明，在体细胞中，复制应激后会发生 MDC1 依赖性 γH2AX 信号的扩增，并且与转录沉默有关。我们提出，一个共同的 DDR 途径是 MSCI 和体细胞对复制应激反应的基础。这些结果表明，以 MDC1 为中心的 DDR 途径触发了生殖细胞中性染色体的表观遗传沉默。
