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bioRxiv · 10.1101/2021.01.03.425167

B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells

Yu, B.·Qi, Y.·Li, R.·Shi, Q.·Satpathy, A.·Chang, H. Y.
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Abstract

The long noncoding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-specific XIST complexes, and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. XIST dysregylation, reflected by escape of XIST-dependent genes, occurs in CD11c+ atypical memory B cells across single-cell transcriptome data in patients with female-biased autoimmunity and COVID-19 infection. XIST inactivation with TLR7 agonism suffices to promote isotype-switched atypical B cells. These results suggest cell-type-specific diversification of lncRNA-protein complexes increase lncRNA functionalities, and expand roles for XIST in sex-differences in biology and medicine. HIGHLIGHTSO_LIXIST prevents escape of genes with DNA hypomethylated promoters in B cells. C_LIO_LIXIST maintains X-inactivation through continuous deacetylation of H3K27ac. C_LIO_LIXIST ChIRP-MS and allelic CRISPRi screen reveal a B cell-specific XIST cofactor TRIM28. C_LIO_LIXIST loss and TLR7 stimulation promotes CD11c+ atypical B cell formation. C_LI

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Yu, B., Qi, Y., Li, R., Shi, Q., Satpathy, A., Chang, H. Y.. 2021-01-04. B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells. https://doi.org/10.1101/2021.01.03.425167

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