Inversion of a topological domain leads to restricted changes in its gene expression and affects interdomain communication.
Inversion of a topological domain leads to restricted changes in its gene expression and affects interdomain communication.
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DOI：
10.1242/dev.200568
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发表时间：
2022-05-01
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--
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基因组的拓扑结构和基因表达调控之间的相互作用仍不清楚。拓扑相关结构域（TADs）的分子因子（如CTCF）的缺失导致基因表达的适度改变，而涉及边界的基因组重排破坏了正常的基因表达，并可能导致病理表型。在这里，我们针对的是非编码转录本Xist的邻近区域，它控制X染色体失活。倒置245 kb内的CTCF的接触，但发现异质性的“接触”的潜力不同的CTCF网站的预期重排。 其中大多数基因的表达在小鼠胚胎干细胞和分化过程中保持不受影响。有趣的是，Xist的表达异位上调。在小鼠胚胎中的相同倒位导致偏向的Xist表达。CTCF簇较小的倒位和缺失导致了类似的结果：接触重排和局部基因表达的有限变化，但在胚胎中Xist表达的显着变化。我们的研究表明，布线的监管相互作用内的一个TADs可以影响相邻的TADs中的基因表达，突出了存在的机制，跨TADs通信。总结：在小鼠胚胎和胚胎干细胞中使用基因组工程，发现调节X失活的Xist的表达对相邻染色体的拓扑变化敏感。
The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, whereas genomic rearrangements involving TAD boundaries disrupt normal gene expression and can lead to pathological phenotypes. Here, we targeted the TAD neighboring that of the noncoding transcript Xist, which controls X-chromosome inactivation. Inverting 245 kb within the TAD led to expected rearrangement of CTCF-based contacts but revealed heterogeneity in the ‘contact’ potential of different CTCF sites. Expression of most genes therein remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression of Xist was ectopically upregulated. The same inversion in mouse embryos led to biased Xist expression. Smaller inversions and deletions of CTCF clusters led to similar results: rearrangement of contacts and limited changes in local gene expression, but significant changes in Xist expression in embryos. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighboring TADs, highlighting the existence of mechanisms of inter-TAD communication. Summary: Using genomic engineering in mouse embryos and embryonic stem cells, expression of Xist, which regulates X-inactivation, is found to be sensitive to topological changes in the neighboring TAD.
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