CTCF公司
粘蛋白
染色质
重组
基因座(遗传学)
V(D)J复合
生物
分子生物学
遗传学
DNA
细胞生物学
转录因子
基因
增强子
作者
Zhaoqing Ba,Jing Lou,Adam Yongxin Ye,Hai-Qiang Dai,Edward W. Dring,Sherry Lin,Suvi Jain,Nia Kyritsis,Kyong-Rim Kieffer-Kwon,Rafael Casellas,Frederick W. Alt
出处
期刊:Nature
[Springer Nature]
日期:2020-07-27
卷期号:586 (7828): 305-310
被引量:84
标识
DOI:10.1038/s41586-020-2578-0
摘要
The RAG endonuclease initiates Igh locus V(D)J recombination in progenitor (pro)-B cells1. Upon binding a recombination centre-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJH-based recombination centre2. CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG scanning3–5; however, their inactivation allows scanning to proximal VHs, where additional CBEs activate rearrangement and impede scanning any further upstream5. Distal VH utilization is thought to involve diffusional access to the recombination centre following large-scale Igh locus contraction6–8. Here we test the potential of linear RAG scanning to mediate distal VH usage in G1-arrested v-Abl pro-B cell lines9, which undergo robust D-to-JH but little VH-to-DJH rearrangements, presumably owing to lack of locus contraction2,5. Through an auxin-inducible approach10, we degraded the cohesin component RAD2110–12 or CTCF12,13 in these G1-arrested lines. Degradation of RAD21 eliminated all V(D)J recombination and interactions associated with RAG scanning, except for reecombination centre-located DQ52-to-JH joining, in which synapsis occurs by diffusion2. Remarkably, while degradation of CTCF suppressed most CBE-based chromatin interactions, it promoted robust recombination centre interactions with, and robust VH-to-DJH joining of, distal VHs, with patterns similar to those of ‘locus-contracted’ primary pro-B cells. Thus, downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG scanning across the 2.7-Mb Igh locus. Using an auxin-inducible approach, the authors show that downmodulation of CTCF activity promotes cohesin-driven RAG endonuclease scanning, and thus V(D)J recombination, across the Igh locus.
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