Research ArticleANTIBODIES

Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination

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Science Immunology  07 Feb 2020:
Vol. 5, Issue 44, eaay5864
DOI: 10.1126/sciimmunol.aay5864

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“Lnc”ing class switch recombination

Besides protein-coding transcripts, a number of transcripts, including microRNAs and ribosomal RNAs, have noncoding functions. One of the less understood classes of noncoding transcripts are long noncoding RNAs (lncRNAs). Rothschild et al. have identified lncRNA-CSRIgA, an lncRNA ~2.6 megabases downstream of immunoglobulin heavy-chain locus, to be a regulator of class switch recombination (CSR). Deletion of lncRNA-CSRIgA impaired class switching in B cells, particularly to the IgA isotype. Deletion of the genomic region encoding lncRNA-CSRIgA not only abrogates transcription but also results in loss of cis-regulatory functions. Lentiviral expression of lncRNA-CSRIgA rescued class switching in lncRNA-CSRIgA–deficient B cells, strongly suggesting that lncRNA does have a functional role in promoting class switch recombination.

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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