美国哈佛医学院Frederick W. Alt、Zhaoqing Ba等研究人员合作发现,CTCF介导长距离黏连蛋白驱动的V(D)J重组扫描。该项研究成果于2020年7月27日在线发表在《自然》杂志上。
Title: CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning
Author: Zhaoqing Ba, Jiangman Lou, Adam Yongxin Ye, Hai-Qiang Dai, Edward W. Dring, Sherry G. Lin, Suvi Jain, Nia Kyritsis, Kyong-Rim Kieffer-Kwon, Rafael Casellas, Frederick W. Alt
Issue&Volume: 2020-07-27
Abstract: RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells1. Upon binding a recombination center (RC)-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin, to locate Ds and assemble a DJH-based RC2. CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning3–5; but 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 RC access 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 due to lack of locus contraction2,5. Through an auxin-inducible approach10, we degrade the cohesin-component Rad2110–12 or CTCF12,13 in these G1-arrested lines. Rad21 degradation eliminated all V(D)J recombination and RAG-scanning-associated interactions, except RC-located DQ52-to-JH joining in which synapsis occurs by diffusion2. Remarkably, while CTCF degradation suppressed most CBE-based chromatin interactions, it promoted robust RC interactions with, and robust VH-to-DJH joining of, distal VHs, with patterns similar to those of "locus-contracted" primary pro-B cells. Thus, down-modulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG-scanning across the 2.7Mb Igh locus.
DOI: 10.1038/s41586-020-2578-0
Source: https://www.nature.com/articles/s41586-020-2578-0
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html
本期文章:《自然》:Online/在线发表