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

Yu, Bingfei; Qi, Yanyan; Li, Rui; Shi, Quanming; Satpathy, Ansuman T.; Chang, Howard Y.

doi:10.1101/2021.01.03.425167

2021

DOI: 10.1101/2021.01.03.425167

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

Bingfei Yu

Yanyan Qi

Rui Li

et al.

Abstract: SUMMARYThe 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 complexe… Show more

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Cited by 3 publications

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Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Ricker

Manni

Flores-Castro

et al. 2021

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Sex differences characterize immune responses to viruses like SARS-CoV2 and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c− effector populations with pathogenic and proinflammatory potential. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

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Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Ricker

Manni

Flores-Castro

et al. 2021

Preprint

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Prognostic Roles of LncRNA XIST and Its Potential Mechanisms in Human Cancers: A Pan-Cancer Analysis

Wang

Shi

et al. 2021

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Background: X-inactive specific transcript (XIST), it has been found, is abnormal expression in various neoplasms. This work aims to explore its potential molecular mechanisms and prognostic roles in types of malignancies. Methods: This research comprehensively investigated XIST transcription across cancers from Oncomine, TIMER 2.0 and GEPIA2. Correlations of XIST expression with prognosis, miRNAs, interacting protens, immune infiltrates, checkpoint markers and mutations of tumor-associated genes were also analyzed by public databases. Results: Compared to normal tissues, XIST was lower in BRCA, COAD, LUAD, lymphoma and OV in Oncomine; In TIMER 2.0, XIST was decreased in BRCA, KICH, THCA and UCEC, but increased in KIRC and PRAD; In GEPIA2, XIST was down-regulated in CESC, COAD, OV, READ, STAD, UCEC and UCS. Public databases also showed that XIST was a good indicator of prognosis in BRCA, CESC, COAD, STAD, OV and so on, but a bad one in KIRC, KIRP and so on. From starBase, we found 29 proteins interacting with XIST, and identified 4 miRNAs, including miR-103a-3p, miR-107, miR-130b-3p and miR-96-5p, which might be sponged by XIST in cancers. Furthermore, XIST was linked with immune infiltration, especially T cell CD4+, and was related to over 20 immune checkpoint markers. In addition, XIST was associated with several tumor-associated gene mutations in some cancers. Conclusion: In summary, abnormal expression of XIST influenced prognosis, miRNAs, immune cell infiltration and mutations of tumor-associated genes across cancers, especially BRCA and colorectal cancer. More efforts should be made to detect potential molecular mechanisms of XIST in the carcinogenesis.

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Xist expression impacts chromatin structure and YY1 mediated transcription of X-linked genes in hematopoietic progenitor cells

Yang

Yildirim

2022

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X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for genes that escape XCI. This inactive state is propagated during cell divisions with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here, we delete Xist in hematopoietic cells of mice and report increased fraction of cycling hematopoietic progenitors and differentiation defects during hematopoiesis. Xist loss results in upregulation of a subset of X-linked genes, several of which escape XCI and have functions in hematopoiesis and immunity. We find that the underlying mechanism of transcriptional upregulation involves reduced H3K27me3 occupancy and increased chromatin accessibility which accommodate binding of YY1 transcription factor (TF). We propose that XCI maintenance defects in Xist deficient mice rely on the landscape of open chromatin sites, TF availability, and cell cycle stress in specific cellular context during hematopoiesis.

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

Cited by 3 publications

References 91 publications

Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis

Prognostic Roles of LncRNA XIST and Its Potential Mechanisms in Human Cancers: A Pan-Cancer Analysis

Xist expression impacts chromatin structure and YY1 mediated transcription of X-linked genes in hematopoietic progenitor cells

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