Background/Purpose: Systemic lupus erythematosus (SLE) is characterized by multiple B cell abnormalities, including the production of autoantibodies, a major contributing factor to disease pathogenesis. Epigenetic modifications that drive the early molecular events leading to the activation of autoreactive B cells in SLE remain unclear. Therefore, we investigated the epigenetic and transcriptional signatures of SLE B cell subsets including activated naïve (aN), resting naïve (rN), late transitional (T3), switched memory (SM), and double negative (DN) B cells.

Methods: We simultaneously profiled the methylome and transcriptome of B cell subsets from SLE and healthy control (HC) African American females utilizing reduced representation bisulfite sequencing (RRBS) and RNA-seq, respectively. In addition, chromatin accessibility in SLE and HC B cells subsets was determined using assay for transposase-accessible chromatin (ATAC)-seq.

Results: Global DNA methylation analysis of total B cells identified 2,686 SLE-disease specific differentially methylated loci surrounding 951 genes. Demethylated genes in SLE B cells included IFN response genes as well as negative regulators of the viral response, while cell-cell signaling and calcium transmembrane transport genes were methylated. SLE and HC aN B cells gained DNA methylation at 2,952 loci and lost DNA methylation at 82,313 loci when compared compared to rN B cells, indicating a loss of DNA methylation during the transition from a rN to an aN B cell state. Transcriptome analysis of total B cells identified 334 differentially regulated genes in SLE patients. In individual B cell subsets, 953 genes were differentially regulated between B cell types; these cell-type transciptomes diverged from one another as cells differentiated from rN to aN to DN B cells. Integrated analysis of the methylome and transcriptome data sets identified 85 genes, 35 of which were IFN-regulated genes, whose DNA methylation changes inversely correlated with SLE disease-specific changes in gene expression.

Conclusion: DNA methylation analysis indicated the largest differences between cell types with aN B cells undergoing a genome-wide hypomethylation. Transcriptionally aN and rN B cells are more similar to each other, whereas DN B cells are more disparate. This could reflect the cell stage of activation/differentiation, as we hypothesize that differentiation occurs in a linear manner from rN to aN to DN B cells. Although the largest differences were observed between B cell types, there were consistent SLE-specific gene expression differences (i.e.: IFN). Our results indicate that SLE B cells are epigenetically and transcriptionally distinct from HC B cells, suggesting that SLE B cells may be pathogenically programmed at an early stage of maturation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-subsets-are-epigenetically-and-transcriptionally-dysregulated-in-systemic-lupus-erythematosus/