Spatial partitioning of the regulatory landscape of the X-inactivation centre.
Spatial partitioning of the regulatory landscape of the X-inactivation centre.
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DOI：
10.1038/nature11049
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发表时间：
2012-04-11
期刊：
影响因子：
64.8
通讯作者：
Heard, Edith
中科院分区：
文献类型：
--
作者：
Nora, Elphege P.;Lajoie, Bryan R.;Schulz, Edda G.;Giorgetti, Luca;Okamoto, Ikuhiro;Servant, Nicolas;Piolot, Tristan;van Berkum, Nynke L.;Meisig, Johannes;Sedat, John;Gribnau, Joost;Barillot, Emmanuel;Bluethgen, Nils;Dekker, Job;Heard, Edith
小鼠X失活中心（Xic）通过控制非编码Xist转录物的表达来协调X失活的启动。然而，Xist的监管格局仍有待确定。在这里，我们使用染色体构象捕获碳拷贝和超分辨率显微镜来分析包括Xist在内的4.5Mb区域的空间组织。我们发现了一系列离散的200 kb-1 Mb拓扑相关结构域（TADs），它们存在于细胞分化之前和之后以及活性和非活性X上。这些结构域与几个全域表观基因组特征以及共调控基因簇对齐。一个染色体边界的破坏导致异位染色体接触和长距离转录失调。Xist/Tsix说明了空间分离的相反调节的染色体邻居，其启动子位于两个相邻的TAD，每个含有其已知的正调节。这导致了Tsix的远端调控区的鉴定，该调控区在其胞内产生一种新的长插入RNA Linx。除了揭示哺乳动物染色体顺式调控结构的新原理外，我们的研究还为Xic的完整遗传解剖奠定了基础。
The mouse X-inactivation center (Xic) orchestrates initiation of X inactivation by controlling the expression of the non-coding Xist transcript. The full extent of Xist’s regulatory landscape remains to be defined however. Here we use Chromosome Conformation Capture Carbon-Copy and super-resolution microscopy to analyse the spatial organisation of a 4.5Mb region including Xist. We uncover a series of discrete 200kb-1Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. These domains align with several domain-wide epigenomic features as well as co-regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional mis-regulation. Xist/Tsix illustrates the spatial segregation of oppositely regulated chromosomal neighborhoods, with their promoters lying in two adjacent TADs, each containing their known positive regulators. This led to the identification of a distal regulatory region of Tsix producing a novel long intervening RNA, Linx, within its TAD. In addition to uncovering a new principle of the cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the Xic.
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