Howard Hughes Medical Institute, Boston, Massachusetts, USA.
Nat Struct Mol Biol. 2011 Dec 4;19(1):56-61. doi: 10.1038/nsmb.2195.
Dosage compensation in mammals occurs at two levels. In addition to balancing X-chromosome dosage between males and females via X inactivation, mammals also balance dosage of Xs and autosomes. It has been proposed that X-autosome equalization occurs by upregulation of Xa (active X). To investigate mechanism, we perform allele-specific ChIP-seq for chromatin epitopes and analyze RNA-seq data. The hypertranscribed Xa demonstrates enrichment of active chromatin marks relative to autosomes. We derive predictive models for relationships among Pol II occupancy, active mark densities and gene expression, and we suggest that Xa upregulation involves increased transcription initiation and elongation. Enrichment of active marks on Xa does not scale proportionally with transcription output, a disparity explained by nonlinear quantitative dependencies among active histone marks, Pol II occupancy and transcription. Notably, the trend of nonlinear upregulation also occurs on autosomes. Thus, Xa upregulation involves combined increases of active histone marks and Pol II occupancy, without invoking X-specific dependencies between chromatin states and transcription.
哺乳动物中的剂量补偿发生在两个层面上。除了通过 X 染色体失活来平衡雌雄两性之间的 X 染色体剂量外，哺乳动物还平衡 X 染色体和常染色体的剂量。有人提出，X-常染色体的平衡是通过 Xa（活性 X）的上调来实现的。为了研究机制，我们对染色质表位进行了特定等位基因的 ChIP-seq 分析，并对 RNA-seq 数据进行了分析。与常染色体相比，过度转录的 Xa 表现出活跃染色质标记的富集。我们推导了 Pol II 占有率、活性标记密度和基因表达之间关系的预测模型，并提出 Xa 的上调涉及转录起始和延伸的增加。Xa 上活性标记的富集与转录输出不成比例，这种差异可以通过活性组蛋白标记、Pol II 占有率和转录之间的非线性定量关系来解释。值得注意的是，这种非线性上调的趋势也发生在常染色体上。因此，Xa 的上调涉及活性组蛋白标记和 Pol II 占有率的联合增加，而不需要在染色质状态和转录之间引入 X 染色体特异性的依赖关系。
