The Histone Demethylase LSD1 Regulates B Cell Proliferation and Plasmablast Differentiation

J Immunol. 2018 Nov 1;201(9):2799-2811. doi: 10.4049/jimmunol.1800952. Epub 2018 Sep 19.

Abstract

B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM. LSD1-deficient PB exhibited derepression and superinduction of genes involved in immune system processes; a subset of these being direct Blimp-1 target-repressed genes. Cell cycle genes were globally downregulated without LSD1, which corresponded to a decrease in the proliferative capacity of LSD1-deficient activated B cells. PB lacking LSD1 displayed increased histone H3 lysine 4 monomethylation and chromatin accessibility at nB active enhancers and the binding sites of transcription factors Blimp-1, PU.1, and IRF4 that mapped to LSD1-repressed genes. Together, these data show that LSD1 is required for normal in vivo PB formation, distinguish LSD1 as a transcriptional rheostat and epigenetic modifier of B cell differentiation, and identify LSD1 as a factor responsible for decommissioning nB active enhancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Cell Proliferation / physiology
  • Histone Demethylases / immunology*
  • Mice
  • Plasma Cells / cytology*
  • Plasma Cells / immunology

Substances

  • Histone Demethylases
  • KDM1a protein, mouse