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研究发现Pax5促进V基因重组机制
2020-07-03 11:11

奥地利维也纳生物中心(VBC)分子病理研究所(IMP)Meinrad Busslinger研究组近日取得一项新成果。他们发现Wapl 抑制 Pax5,从而促进免疫球蛋白重链(Igh)环挤压造成的V基因的重组。该研究于2020年7月1日发表于《自然》。

他们证明基因座收缩是由整个Igh基因座上的环挤出引起的。值得注意的是,在pro-B和pre-B细胞中,Wapl的表达被Pax5特异性抑制,通过增加黏着蛋白在染色质上的停留时间,促进了延伸的环挤出。Pax5通过募集多梳抑制复合物2,在Wapl启动子处诱导二价染色质,通过单个Pax5结合位点介导Wapl的转录抑制。Wapl表达降低会导致染色体结构发生整体变化,这表明重组所有V基因的潜力,导致pro-B细胞中整个基因组的结构发生变化。

据介绍,诸如V(D)J重组之类的核过程是由多个层次的染色体的三维组织精心编排的,包括区室和由染色质环组成的拓扑相关域(TAD)。通过染色质环挤出形成TAD,这取决于环状粘着蛋白复合物的环挤出功能。相反,粘着素释放因子Wapl4限制环的延伸。提供对病原体具有体液免疫力的多样化抗体库,需要所有V基因参与V(D)J重组,这取决于Pax517对2.8 Mb Igh基因座的收缩,但是,Pax5如何控制pro-B细胞中的Igh收缩仍然未知。

附:英文原文

Title: Wapl repression by Pax5 promotes V gene recombination by Igh loop extrusion

Author: Louisa Hill, Anja Ebert, Markus Jaritz, Gordana Wutz, Kota Nagasaka, Hiromi Tagoh, Daniela Kostanova-Poliakova, Karina Schindler, Qiong Sun, Peter Bnelt, Maria Fischer, Jan-Michael Peters, Meinrad Busslinger

Issue&Volume: 2020-07-01

Abstract: Nuclear processes, such as V(D)J recombination, are orchestrated by the three-dimensional organization of chromosomes at multiple levels, including compartments1 and topologically associated domains (TADs)2,3 consisting of chromatin loops4. TADs are formed by chromatin-loop extrusion5,6,7, which depends on the loop-extrusion function of the ring-shaped cohesin complex8,9,10,11,12. Conversely, the cohesin-release factor Wapl13,14 restricts loop extension10,15. The generation of a diverse antibody repertoire, providing humoral immunity to pathogens, requires the participation of all V genes in V(D)J recombination16, which depends on contraction of the 2.8-Mb-long immunoglobulin heavy chain (Igh) locus by Pax517,18. However, how Pax5 controls Igh contraction in pro-B cells remains unknown. Here we demonstrate that locus contraction is caused by loop extrusion across the entire Igh locus. Notably, the expression of Wapl is repressed by Pax5 specifically in pro-B and pre-B cells, facilitating extended loop extrusion by increasing the residence time of cohesin on chromatin. Pax5 mediates the transcriptional repression of Wapl through a single Pax5-binding site by recruiting the polycomb repressive complex 2 to induce bivalent chromatin at the Wapl promoter. Reduced Wapl expression causes global alterations in the chromosome architecture, indicating that the potential to recombine all V genes entails structural changes of the entire genome in pro-B cells.

DOI: 10.1038/s41586-020-2454-y

Source: https://www.nature.com/articles/s41586-020-2454-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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

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