PionX sites mark the X chromosome for dosage compensation
PionX sites mark the X chromosome for dosage compensation
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DOI：
10.1038/nature19338
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发表时间：
2016-09-08
期刊：
影响因子：
64.8
通讯作者：
Becker, Peter B.
中科院分区：
文献类型：
--
作者：
Villa, Raffaella;Schauer, Tamas;Becker, Peter B.
定义哪一小部分相关DNA序列可以被转录因子选择性结合的规则知之甚少。DNA识别中最具挑战性的任务之一是剂量补偿系统，该系统需要区分性染色体和常染色体。在黑腹果蝇中，雄性特异性致死剂量补偿复合物（MSL-DCC）使单个雄性X染色体的转录水平加倍，但这种选择性的性质尚不清楚（1）。先前鉴定X染色体特异性靶序列的努力是不成功的，因为鉴定的MSL识别元件缺乏区分能力（2，3）。因此，已经提出了额外的决定因素，如辅因子、染色质特征、RNA和染色体构象，以进一步细化靶向（4）。在这里，使用体外全基因组DNA结合试验，我们表明，识别的X染色体是一个内在的功能的MSL-DCC。MSL 2，男性特异性组织者的复杂，使用两个不同的DNA相互作用表面的CXC和脯氨酸/碱性残基丰富的结构域，以确定复杂的X染色体上的DNA元素。特异性由CXC结构域提供，其结合由DNA序列和形状定义的新基序。该基序表征了MSL 2结合位点的一个亚类，我们将其命名为PionX（X染色体上的先驱位点），因为它们在D.米兰达和是在从头MSL-DCC组装期间结合的第一个染色体位点。我们的数据提供了第一个，据我们所知，记录的分子机制，通过剂量补偿机制区分X染色体的常染色体。他们强调了蛋白质识别复杂DNA元件的基本原则，这将对染色体生物学的许多方面产生强烈影响。
The rules defining which small fraction of related DNA sequences can be selectively bound by a transcription factor are poorly understood. One of the most challenging tasks in DNA recognition is posed by dosage compensation systems that require the distinction between sex chromosomes and autosomes. In Drosophila melanogaster, the male-specific lethal dosage compensation complex (MSL-DCC) doubles the level of transcription from the single male X chromosome, but the nature of this selectivity is not known(1). Previous efforts to identify X-chromosome-specific target sequences were unsuccessful as the identified MSL recognition elements lacked discriminative power(2,3). Therefore, additional determinants such as co-factors, chromatin features, RNA and chromosome conformation have been proposed to refine targeting further(4). Here, using an in vitro genome-wide DNA binding assay, we show that recognition of the X chromosome is an intrinsic feature of the MSL-DCC. MSL2, the male-specific organizer of the complex, uses two distinct DNA interaction surfaces-the CXC and proline/basic-residue-rich domains-to identify complex DNA elements on the X chromosome. Specificity is provided by the CXC domain, which binds a novel motif defined by DNA sequence and shape. This motif characterizes a subclass of MSL2-binding sites, which we name PionX (pioneering sites on the X) as they appeared early during the recent evolution of an X chromosome in D. miranda and are the first chromosomal sites to be bound during de novo MSL-DCC assembly. Our data provide the first, to our knowledge, documented molecular mechanism through which the dosage compensation machinery distinguishes the X chromosome from an autosome. They highlight fundamental principles in the recognition of complex DNA elements by protein that will have a strong impact on many aspects of chromosome biology.