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:
- 金额:$ 3.52万
- 依托单位:
- 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
- 来源:
- 关键词:AgeAllelesAntibodiesAutoantibodiesAutoimmune DiseasesAutoimmunityB cell differentiationB-Cell ActivationB-Lymphocyte SubsetsB-LymphocytesBiological AssayBreedingCell CompartmentationCell physiologyCellsCellular biologyCharacteristicsChemicalsComplexDataDepositionDevelopmentDiagnosisDiseaseDosage Compensation (Genetics)EndosomesEpigenetic ProcessFemaleGene DosageGene ExpressionGene SilencingGenesGeneticGenetic TranscriptionHeightHistonesHumanImmuneImpairmentIndividualInjectionsKlinefelter&aposs SyndromeLaboratory FindingLinkLymphocyteMaintenanceMammalsMediatingModelingMusPathogenesisPathway interactionsPatientsPersonsPhenotypePlayPopulationPredispositionPristaneProductionProliferatingRNARegulator GenesResearch ProposalsRoleSex BiasSignal TransductionSomatic CellStimulusSystemic Lupus ErythematosusTLR7 geneTestingTimeUntranslated RNAUp-RegulationVisualizationWomanX ChromosomeX Inactivationcell typedosageds-DNAexperimental studyimmunoregulationimprovedin vitro Assayinsightmembermenmouse modelnovelrecruitresponserisk varianttranscriptome sequencing
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
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