Epigenetic programming underpins B cell dysfunction in human SLE

• Type of Material: Article
• Authors: Christopher Scharer, Emory University; Emily L Blalock, Emory University; Tian Mi, Emory University; Benjamin G Barwick, Emory University; Scott Jenks, Emory University; Arezou Khosroshahi, Emory University; Frances Lee, Emory University; Ignacio Sanz, Emory University; Jeremy Boss, Emory University
• Language: English
• Date: 2019-08-01
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-019-0419-9
• Title of Journal or Parent Work: NATURE IMMUNOLOGY
• Volume: 20
• Issue: 8
• Start Page: 1071
• End Page: +
• Grant/Funding Information: This work was supported by NIH U19 AI110483 to J.M.B. and I.S., P01 AI125180 to I.S., E.H.L., and J.M.B., RO1 AI113021 to J.M.B., F31 AI112261 to B.G.B., and T32 GM008490 to J.M.B.
• Keywords: COMPLEXES; Life Sciences & Biomedicine; TRANSCRIPTION FACTORS; Immunology; EVOLUTION; Science & Technology; CHROMATIN; GROWTH; POPULATION; GENE-EXPRESSION; RESPONSES; RECEPTOR; DIFFERENTIATION
• Research Categories: Health Sciences, Immunology; Biology, Genetics

Abstract

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.