YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment.
YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment.
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DOI：
10.1101/gr.215160.116
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发表时间：
2017-07
期刊：
影响因子：
7
通讯作者：
Phillips-Cremins JE
中科院分区：
文献类型：
--
作者：
Beagan JA;Duong MT;Titus KR;Zhou L;Cao Z;Ma J;Lachanski CV;Gillis DR;Phillips-Cremins JE
CTCF是一种结构蛋白，在连接多能干细胞中的高阶染色质折叠中具有关键作用。最近的报告表明，CTCF结合是更动态的发展过程中比以前认识到的。在这里，我们着手了解在早期神经谱系定型过程中，全基因组CTCF占用的变化在多大程度上有助于精细尺度染色质折叠的3D重构。出乎意料的是，我们观察到在从幼稚/致敏的多能性向多能原代神经祖细胞（NPC）过渡期间CTCF占据率急剧下降。许多多能性基因-增强子相互作用由CTCF锚定，并且其占用率在分化期间与环退役平行地丧失。相反，NPC中的CTCF结合位点在多能干细胞中基本上预先存在。只有少数CTCF位点在NPC中重新出现。我们确定了另一个锌指蛋白，阴阳1（YY 1），在NPC特异性基因和增强子之间的相互作用的基础上循环。推定的NPC特异性增强子在参与3D接触时表现出强的YY 1信号，而不在环中时表现出可忽略的YY 1信号。此外，Yy 1的siRNA敲低特异性地破坏关键NPC增强子与其靶基因之间的相互作用。YY 1介导的NPC调控元件之间的相互作用通常嵌套在由CTCF锚定的组成性环内。总之，我们的研究结果支持一个模型，其中YY 1作为一个建筑蛋白连接发育调节循环的相互作用，YY 1介导的相互作用的位置可以划分在发展中的一个预先存在的拓扑结构框架创建的组成性CTCF介导的相互作用。
CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.