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研究揭示TAD结构在调控基因表达中的作用
来源:小柯机器人 发布时间:2019/8/5 16:05:22

近日,德国马克斯·普朗克分子遗传学研究所Daniel M. Ibrahim和Stefan Mundlos团队合作,以Sox9-Kcnj2基因座为模型揭示了TAD结构的功能。相关论文于2019年8月发表在《自然—遗传学》上。

研究人员测试了Sox9-Kcnj2基因座的TAD在小鼠枝芽发育中的功能。研究人员发现,去除TAD内以及边界的主要CTCF位点会导致相邻TAD的融合,但对基因表达无明显影响。然而,将TAD的边界进行反转和/或重定位会改变调控活性,从而产生基因错误表达与疾病表型。因此,TAD结构为基因的表达提供了稳定性与精确性,但对于发育中的基因调控并不是必需的。疾病相关基因的异常激活并不是仅仅由转录绝缘性丢失所引起,而是需要CTCF依赖的增强子-启动子联系的重定向。

据介绍,通过cohesin与DNA结合因子CTCT的合作,基因组被组织为三维的单元,这被称为拓扑相关结构域(TAD)。TAD的基因组重排被证明会导致基因的错误表达与疾病,但全基因组敲除CTCF却不会对转录产生明显的影响。


Title: Functional dissection of the Sox9 – Kcnj2 locus identifies nonessential and instructive roles of TAD architecture

Author: Alexandra Despang, Robert Schpflin, Martin Franke, Salaheddine Ali, Ivana Jerkovi, Christina Paliou, Wing-Lee Chan, Bernd Timmermann, Lars Wittler, Martin Vingron, Stefan Mundlos, Daniel M. Ibrahim

Issue&Volume: 2019-07-29

Abstract: The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9Kcnj2 locus. We show that the removal of all major CTCF sites at the boundary and within the TAD resulted in a fusion of neighboring TADs, without major effects on gene expression. Gene misexpression and disease phenotypes, however, were achieved by redirecting regulatory activity through inversions and/or the repositioning of boundaries. Thus, TAD structures provide robustness and precision but are not essential for developmental gene regulation. Aberrant disease-related gene activation is not induced by a mere loss of insulation but requires CTCF-dependent redirection of enhancerpromoter contacts.

DOI: 10.1038/s41588-019-0466-z

Source:https://www.nature.com/articles/s41588-019-0466-z

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Volume 51 Issue 8