Exploring the transcriptional impact of ERα in the B cell response of systemic lupus erythematosus

Abstract Systemic lupus erythematosus (SLE) is a heterogeneous, autoimmune disease. Being female is a significant, baseline risk factor for developing lupus. The mechanisms responsible for enhanced risk remain unknown. The nuclear hormone receptor and key transcription factor, estrogen receptor alpha (ERα), has a number of immune gene targets; yet, understanding of its regulation of the immune response is incomplete. Lupus prone mice, expressing a truncated functional ERα knockout, survived longer and had reduced renal disease. However, a complete knockout of ERα was not protective. Our goal is to identify the molecular mechanisms utilized by ERα in regulating the immune response in lupus B cells. We identified ERα associated genes and determined expression differences in B cells isolated from female African American (AA) lupus patients. RNA-seq analysis indicates that 60% of ERα target genes were deferentially expressed and 82% of these genes were upregulated in patients compared to controls. To understand ERα function, full-length ERα and an isoform, ERα46 (lacking the AF-1 activation domain), were transfected into an EBV transformed SLE B cell line and the expression of ERα gene targets, including inflammatory cytokines (IL1β and IL6) examined. Transfection results varied by gene and suggest the interaction between ERα isoforms is complex. The effect of epigenetic modifying agents on ERα protein expression in transfected SLE B cells was also studied. Evidence suggests that an increase in DNA methylation leads to increased protein expression of ERα isoforms. The regulatory role of ERα in lupus B cells is complex, involves epigenetic changes and interplay between isoforms. Results support a role for ERα in the pathogenesis of SLE.