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Author Notes:

See publication for full list of authors.

Correspondence to Jeremy M. Boss, jmboss@emory.edu, or Iñaki Sanz, ignacio.sanz@emory.edu

Author contributions: C.D.S. and E.L.B. designed and performed experiments, analyzed the data, and wrote the manuscript.

B.G.B. and T.M. analyzed data.

D.G.P. performed ATAC-seq.

S.A.J. performed PD-1 and ATF3 phenotyping.

T.D., K.S.C, and S.L.H. sorted and prepared cDNA for validation cohorts.

B.E.N., E.-H.L., and C.W. provided cell sorting, biobanking expertise, and sample preparation.

A.K. evaluated cohort clinical data.

I.S. and J.M.B. designed experiments, wrote the manuscript, and oversaw the project.

We thank the members of the Boss and Sanz laboratories for critical reading of the manuscript, the New York University Genome Technology Center for Illumina sequencing, the Yerkes Genomics Core for RNA-seq library preparation, the Emory Pediatrics Flow Cytometry core for FACS isolation of cell subsets, and the Emory Integrated Genetics and Computational Core for Bioanalyzer and sequencing library QC.

The authors declare no competing interests.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • TRANSCRIPTION FACTORS
  • GENE-EXPRESSION
  • DIFFERENTIATION
  • RECEPTOR
  • GROWTH
  • CHROMATIN
  • POPULATION
  • COMPLEXES
  • EVOLUTION
  • RESPONSES

Epigenetic programming underpins B cell dysfunction in human SLE

Journal Title:

NATURE IMMUNOLOGY

Volume:

Volume 20, Number 8

Publisher:

, Pages 1071-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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