Summary
Research on the role of nuclear matrix proteins and DNA methylation in X-Chromosome Inactivation (XCI) maintenance in female lymphocytes and its contribution to systemic lupus erythematosus (SLE).
Role for nuclear matrix proteins and DNA methylation for XCI maintenance in female lymphocytes
US · IL
NIH
grant
awarded
#nih-5R01AI168047-03
What they want
Investigate how Xist-independent DNA methylation maintains transcriptional repression of the Xi and autosomes in naïve B cells, and how alterations in nuclear matrix protein binding promote dynamic XCI maintenance, with a focus on its dysfunction exacerbating Type I IFN-driven lupus disease. This includes three aims: (1) determine if reductions in Xist-independent DNA hypermethylation in naïve B cells are associated with aberrant gene expression in lupus; (2) analyze interactions between SAFB, hnRNPU protein, and Xist RNA in maintaining XCI in B cells and if lupus disease impairs cohesin eviction by hnRNPU-Xist RNA complexes; and (3) assess how impaired XCI maintenance impacts Type I IFN-driven lupus-like disease in female mice.
Deliverables
- Unprecedented mechanistic insight into how biological sex contributes to immune dysregulation of SLE disease
- Identification of new molecular pathways and targets of female-biased autoimmune disease that could be amenable for therapeutic intervention
Technical requirements
- Xist deletion mouse model
- Genetic approaches
- Molecular approaches
