한빛사 논문
Gerson Rothschild1,*, Wanwei Zhang1,*, Junghyun Lim1,*, Pankaj Kumar Giri1,†, Brice Laffleur1, Yiyun Chen2, Mingyan Fang3,4, Yuling Chen5, Lekha Nair1, Zhi-Ping Liu6, Haiteng Deng5, Lennart Hammarström3,4, Jiguang Wang2 and Uttiya Basu1,‡
1 Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
2 Division of Life Science, Department of Chemical and Biological Engineering, Center for Systems Biology and Human Health, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong SAR, China.
3 BGI-Shenzhen, Shenzhen 518083, China.
4 Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
5 School of Life Sciences, Tsinghua University, Beijing 100084, China.
6 Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
* These authors contributed equally to this work.
† Present address: Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
‡ Corresponding author : Uttiya Basu
Abstract
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.
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