B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell-specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3' regulatory region (3'RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome-deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer's patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA ) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3'RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer's patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

中文翻译：

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非编码RNA转录可改变染色体拓扑结构，以促进同种型特异性的类别开关重组。

B细胞经历两种类型的基因组改变以增加抗体多样性：通过体细胞超突变（SHM）将点突变引入免疫球蛋白重链和轻链（IgH和IgL）可变区，以及通过改变表达的IgH常数来改变抗体效应子功能通过IgH类开关重组（CSR）实现区域外显子。SHM和CSR需要B细胞特异性活化诱导的胞苷脱氨酶（AID）蛋白，种系非编码RNA的转录以及3'调控区（3'RR）超级增强子的活性。尽管许多转录调控元件（例如启动子和增强子）位于IgH和IgL序列内部，但问题仍然在于IgH以外的调控元件簇是否控制CSR。使用容易检测到较长的非编码RNA（lncRNA）的RNA外泌体缺陷型小鼠B细胞，我们鉴定了一个由三个RNA表达元件组成的簇，其中包括lncCSRIgA（表达lncRNA-CSRIgA）。从缺乏lncRNA-CSRIgA转录的小鼠模型中分离出的B细胞在Peyer's斑块的B细胞中均无法正常表达CSR对IgA的水平，并且无法在离体培养条件下生长。lncRNA-CSRIgA从增强子位点（lncCSRIgA）表达，以促进将调节蛋白募集到附近的CTCF位点（CTCFlncCSR），从而改变TADlncCSRIgA内的染色体相互作用以及与3'RR超增强子的长期相互作用。与正常人群相比，患有IgA缺乏症的人在lncCSRIgA基因座中表现出多态性。从而，