Kierra Franklin
BME PhD Defense Presentation

Date: 2026-04-14
Time: 1:00 PM
Location / Meeting Link: HSRB I W106 (Rollins Auditorium) https://emory.zoom.us/j/98467399380

Committee Members:
Karmella Haynes, PhD (Advisor); Tara Deans, PhD; Gabe Kwong, PhD; Felipe Quiroz, PhD; Chris Scharer, PhD


Title: Engineering Synthetic Epigenetic Tools for Chromatin Reader Systems to Investigate the SLE-Associated Epigenome

Abstract:
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system is hyperactive and attacks self-tissues. SLE is difficult to study, diagnose, and treat due to its unpredictable symptoms and complex underlying biology. Its higher prevalence in women suggests an X chromosome-linked mechanism. Increasing evidence implicates dysregulated chromatin states as key drivers of aberrant immune cell differentiation and function in SLE, particularly in CD4+ T cells. Chromatin modifications, including DNA methylation and H3K27me3, play central roles in regulating T cell identity, and their disruption contributes to loss of self-tolerance. Methyl-CpG Binding Protein 2 (MeCP2), an X-linked DNA methylation reader, is a validated SLE susceptibility locus, and its overexpression induces autoantibody production in vivo. While DNA methylation and H3K27me3 are typically anti-correlated, emerging studies suggest MeCP2 can associate with H3K27me3 and Polycomb complexes. To address gaps in defining chromatin reader mechanisms, this work uses synthetic biology tools to model and interrogate epigenetic dysregulation. We show CRISPR activation of MeCP2 in CD4+ T cells induced aberrant gene expression, reduced IL2 production, activated IFN genes, and altered Polycomb expression, suggesting crosstalk between DNA methylation and Polycomb machinery. To overcome limitations in H3K27me3 detection, we identified gain-of-function CBX8 mutations and engineered binding domains with enhanced affinity and specificity for H3K27me3. These domains were used to generate fluorescent probes that revealed distinct binding phenotypes and enabled visualization of H3K27me3 patterning in live T cells. Together, these studies define how MeCP2-driven chromatin dysregulation contributes to SLE pathogenesis and provide tools to interrogate its impact on H3K27me3 and Polycomb.