小柯机器人

美国哥伦比亚大学Uttiya Basu研究小组发现，DIS3介导的非编码RNA加工可调节B细胞的染色体结构和体细胞超突变。该研究于2021年2月1日在线发表于国际一流学术期刊《自然—遗传学》。

研究人员开发了一个带条件性等位基因的小鼠模型，可研究RNA外泌体催化亚基DIS3。在DIS3缺陷的B细胞中，免疫球蛋白重链（Igh）基因座在其拓扑相关结构域中的完整性受到影响，并出现与CTCF结合元件侧接的DNA相关RNA的积累、CTCF与CTCF结合元件的结合降低以及黏连蛋白的定位紊乱。缺乏DIS3的B细胞还会积累胞苷脱氨酶介导的不对称缺口，从而改变体细胞超突变模式并增加微同源性介导的末端连接DNA修复。

DIS3缺陷B细胞中突变模式和Igh结构缺陷的改变导致类别转换重组减少，但染色体易位增加。研究人员在Igh位点对DIS3介导的结构调控反映了全基因组的范围，因此表明非编码RNA加工是控制基因组组织的重要机制。 

据悉，非编码RNA可以通过细胞RNA监控机器精确地控制，从而调节各种生物过程。RNA外泌体是哺乳动物细胞中最主要的3'RNA外核糖核酸酶，由9个核心和2个催化亚基组成。

附：英文原文

Title: Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells

Author: Brice Laffleur, Junghyun Lim, Wanwei Zhang, Yiyun Chen, Evangelos Pefanis, Jonathan Bizarro, Carolina R. Batista, Lijing Wu, Aris N. Economides, Jiguang Wang, Uttiya Basu

Issue&Volume: 2021-02-01

Abstract: Noncoding RNAs are exquisitely titrated by the cellular RNA surveillance machinery for regulating diverse biological processes. The RNA exosome, the predominant 3′ RNA exoribonuclease in mammalian cells, is composed of nine core and two catalytic subunits. Here, we developed a mouse model with a conditional allele to study the RNA exosome catalytic subunit DIS3. In DIS3-deficient B cells, integrity of the immunoglobulin heavy chain (Igh) locus in its topologically associating domain is affected, with accumulation of DNA-associated RNAs flanking CTCF-binding elements, decreased CTCF binding to CTCF-binding elements and disorganized cohesin localization. DIS3-deficient B cells also accumulate activation-induced cytidine deaminase–mediated asymmetric nicks, altering somatic hypermutation patterns and increasing microhomology-mediated end-joining DNA repair. Altered mutation patterns and Igh architectural defects in DIS3-deficient B cells lead to decreased class-switch recombination but increased chromosomal translocations. Our observations of DIS3-mediated architectural regulation at the Igh locus are reflected genome wide, thus providing evidence that noncoding RNA processing is an important mechanism for controlling genome organization.

DOI: 10.1038/s41588-020-00772-0

Source: https://www.nature.com/articles/s41588-020-00772-0

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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