Epigenetic programming underpins B cell dysfunction in human SLE

Abstract Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naïve cells. Although these cells have distinct markers and phenotypes, their epigenetic architecture and how it contributes to SLE remains poorly understood. To establish if epigenetic mechanisms contributed to pathogenic B cell programming in SLE, we systematically determined the DNA methylation, chromatin accessibility and transcriptome landscape of human B cell subsets from SLE and healthy subjects. To comprehensively cover the B cell lineage, we isolated resting naïve, activated subsets, class-switched memory, plasmabasts, and a newly defined effector B cell subset. These data define a differentiation hierarchy between the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Intriguingly, an SLE epigenetic signature was already established in resting naïve cells and persisted in more differentiated subsets. DNA methylation profiling revealed a set of CpG surrounding IFN response genes whose methylation status were highly predictive of disease activity. The AP-1 and EGR transcription factor networks were highly enriched in the SLE accessible chromatin and dysregulated genes. Together, these transcription factors acted in synergy with TBET to shape the epigenome of expanded SLE effector B cell subsets. These results provide insights into the epigenetic programming of human B cell subsets, identify loci that correlate with the expansion of distinct pathogenic B cell subsets, and suggest that early alterations in the epigenome may predispose B cells towards a disease fate.