Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, California 94720, USA.
Genes Dev. 2011 Mar 1;25(5):499-515. doi: 10.1101/gad.2016011.
Here we analyze the essential process of X-chromosome dosage compensation (DC) to elucidate mechanisms that control the assembly, genome-wide binding, and function of gene regulatory complexes that act over large chromosomal territories. We demonstrate that a subunit of Caenorhabditis elegans MLL/COMPASS, a gene activation complex, acts within the DC complex (DCC), a condensin complex, to target the DCC to both X chromosomes of hermaphrodites for chromosome-wide reduction of gene expression. The DCC binds to two categories of sites on X: rex (recruitment element on X) sites that recruit the DCC in an autonomous, sequence-dependent manner, and dox (dependent on X) sites that reside primarily in promoters of expressed genes and bind the DCC robustly only when attached to X. We find that DC mutations that abolish rex site binding greatly reduce dox site binding but do not eliminate it. Instead, binding is diminished to the low level observed at autosomal sites in wild-type animals. Changes in DCC binding to these non-rex sites occur throughout development and correlate directly with transcriptional activity of adjacent genes. Moreover, autosomal DCC binding is enhanced by rex site binding in cis in X-autosome fusion chromosomes. Thus, dox and autosomal sites have similar binding potential but are distinguished by linkage to rex sites. We propose a model for DCC binding in which low-level DCC binding at dox sites is dictated by intrinsic properties correlated with high transcriptional activity. Sex-specific DCC recruitment to rex sites then enhances the magnitude of DCC binding to dox sites in cis, which lack high affinity for the DCC on their own. We also show that the DCC balances X-chromosome gene expression between sexes by controlling transcription.
在这里，我们分析了 X 染色体剂量补偿（DC）的基本过程，以阐明控制基因调控复合物组装、全基因组结合和功能的机制，这些复合物作用于大的染色体区域。我们证明，秀丽隐杆线虫 MLL/COMPASS 的一个亚基，即一个基因激活复合物，在 DC 复合物（DCC），即一个凝聚素复合物内发挥作用，将 DCC 靶向到雌雄同体的两条 X 染色体上，以实现全基因组范围内的基因表达降低。DCC 结合到 X 染色体上的两类位点：rex（X 上的募集元件）位点以自主、序列依赖的方式募集 DCC，以及 dox（依赖 X）位点，这些位点主要位于表达基因的启动子中，只有与 X 结合时才强烈结合 DCC。我们发现，消除 rex 位点结合的 DC 突变大大降低了 dox 位点的结合，但并没有完全消除它。相反，结合被降低到在野生型动物中观察到的常染色体位点的低水平。DCC 结合这些非 rex 位点的变化发生在整个发育过程中，并与相邻基因的转录活性直接相关。此外，在 X-常染色体融合染色体中，cis 上的 rex 位点结合增强了常染色体 DCC 的结合。因此，dox 和常染色体位点具有相似的结合潜力，但通过与 rex 位点的连接来区分。我们提出了一个 DCC 结合的模型，其中 dox 位点的低水平 DCC 结合由与高转录活性相关的内在特性决定。然后，sex-specific DCC 对 rex 位点的募集增强了 cis 中 DCC 对 dox 位点的结合程度，而 dox 位点本身对 DCC 没有高亲和力。我们还表明，DCC 通过控制转录来平衡雌雄个体之间的 X 染色体基因表达。
