Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination
| Autor: | Uttiya Basu, Wanwei Zhang, Haiteng Deng, Brice Laffleur, Lekha Nair, Gerson Rothschild, Mingyan Fang, Yiyun Chen, Zhi-Ping Liu, Yuling Chen, Junghyun Lim, Pankaj Kumar Giri, Lennart Hammarström, Jiguang Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Transcriptional Activation
0301 basic medicine RNA Untranslated Immunology Immunoglobulins Somatic hypermutation chemical and pharmacologic phenomena Biology Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Animals Humans Enhancer Mice Knockout B-Lymphocytes Promoter General Medicine Cytidine deaminase Non-coding RNA Chromosomes Mammalian Immunoglobulin Class Switching Cell biology 030104 developmental biology Immunoglobulin class switching CTCF 030220 oncology & carcinogenesis |
| Zdroj: | Sci Immunol |
| ISSN: | 2470-9468 |
| Popis: | 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 lncCSR (IgA) (that expresses lncRNA-CSR(IgA)). B cells isolated from a mouse model lacking lncRNA-CSR(IgA) 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-CSR(IgA) is expressed from an enhancer site (lncCSR(IgA)) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCF(lncCSR)) that alters the chromosomal interactions inside the TAD(lncCSRIgA) and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSR(IgA) locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TAD(lncCSRIgA)) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSR(IgA)) transcription-dependent mechanism. |
| Databáze: | OpenAIRE |
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