B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells.
Bingfei Yu, Yanyan Qi, Rui Li, Quanming Shi, Ansuman T Satpathy, Howard Y Chang
Author Information
Bingfei Yu: Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Yanyan Qi: Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Rui Li: Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Quanming Shi: Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Ansuman T Satpathy: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Howard Y Chang: Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: howchang@stanford.edu.
The long non-coding 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-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.
