Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF
Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF
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DOI：
10.1016/j.molcel.2019.07.039
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发表时间：
2019-11-07
期刊：
影响因子：
16
通讯作者：
Tjian, Robert
中科院分区：
文献类型：
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作者：
Hansen, Anders S.;Hsieh, Tsung-Han S.;Tjian, Robert
哺乳动物基因组被折叠成拓扑相关结构域(TADS)，由CTCF和粘附素锚定的染色质环组成。有些循环是特定于细胞类型的。在这里，我们询问CTCF循环是由通用机制还是特定于位置的机制建立的。在研究CTCF聚簇的分子决定因素时，我们发现CTCF在体外的自结合是RNase敏感的，并且体内的一个内部RNA结合区(RBRi)介导了CTCF聚簇和RNA的相互作用。引人注目的是，删除RBRi会损害mESCs中约一半的染色质环，并导致基因表达的失控。环形成的中断与RBRi突变体CTCF的聚集和染色质结合减少相关，这反过来又导致无法阻止凝集素介导的挤出。因此，CTCF循环至少分为两类：独立于RBR的循环和依赖于RBR的循环。我们推测，RbRi依赖环的证据可能为建立细胞特异性的CTCF环提供了一种分子机制，可能受RNA(S)或其他RbRi相互作用伙伴的调控。
Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBRi) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBRi impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBRi mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBRi-independent and RBR-dependent loops. We speculate that evidence for RBRi-dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBRi-interacting partners.