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Defining the Role of Dynamic X Chromosome Inactivation in Age-Associated B Cells for Female-Biased Systemic Lupus Erythematosus

定义动态 X 染色体失活在年龄相关 B 细胞中对女性系统性红斑狼疮的作用

基本信息

批准号：
10749337
负责人：
Claudia Darnell Lovell
金额：
$ 3.52万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

项目摘要

Project Summary / Abstract 90% of individuals diagnosed with systemic lupus erythematosus (SLE) are women, but the underlying mechanisms that govern sex bias in autoimmune disease are not understood. Susceptibility to SLE increases with the number of X chromosomes carried by an individual, and increased expression of X-linked genes has been found in women with SLE. These findings suggest that gene expression from two X chromosomes likely contributes to female-biased SLE pathogenesis. The dosage of X-linked gene expression in mammals with more than one X chromosome is balanced by epigenetically silencing one X chromosome through X-chromosome inactivation (XCI). XCI is maintained in somatic cells by association of repressive epigenetic features with the inactive X chromosome (Xi), including coating of the Xi with the long non-coding RNA Xist. Despite these repressive features, some genes have been shown to escape silencing from the Xi. Our lab discovered that B cells, a key cell type in SLE pathogenesis, have “dynamic” maintenance of XCI, where naïve B cells lack visible Xist RNA signal yet demonstrate re-localization of Xist RNA to the Xi upon activation. Dynamic XCI maintenance is disrupted and X-linked immune genes are aberrantly expressed in SLE B cells, suggesting that impaired localization of repressive epigenetic marks on the Xi may cause aberrant escape of immune genes from the Xi, enhancing B cell activity. “Age-associated B cells” (ABCs) are emerging as a critical cell type in female-biased autoimmunity and respond robustly to signaling through the TLR7 pathway. Several TLR7 pathway members are X-linked and have been identified as risk variants in SLE. To determine the importance of contributions from the X chromosome in female-biased SLE, I will define epigenetic features of the Xi in ABCs and elucidate the impact of perturbed XCI maintenance in the B cell compartment on SLE pathogenesis. In Aim 1, I hypothesize that ABCs have dynamic XCI maintenance, and that X-linked immune-regulatory genes escape silencing in ABCs. I will isolate murine splenic B cells and visualize the association of repressive epigenetic features with the Xi during differentiation and activation of ABCs and perform allele-specific RNA sequencing to determine genes that escape silencing in ABCs. In Aim 2, I will build on my preliminary data that demonstrates that female mice with a B cell-specific Xist deletion yielding perturbed XCI (“Xist cKO”) are more susceptible to spontaneous and chemically-induced SLE-like disease. I hypothesize that impaired XCI maintenance in female Xist cKO mice leads to upregulation of immune-regulatory X-linked genes, yielding B cells that differentiate more readily into effector populations and produce more antibodies upon stimulation. I will assay transcriptional and functional characteristics of B cells from female Xist cKO mice at steady state and during the development of spontaneous and chemically induced SLE. Investigating the epigenetic mechanisms of XCI maintenance in ABCs will reveal how genetic contributions from the Xi are critical for ABC function, and for the first time will illuminate an X chromosome-based mechanism that underlies female-biased autoimmunity.

项目摘要/摘要