MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis

Nat Commun. 2016 Aug 10;7:12376. doi: 10.1038/ncomms12376.

Abstract

DNA double strand break (DSB) repair is critical for generation of B-cell receptors, which are pre-requisite for B-cell progenitor survival. However, the transcription factors that promote DSB repair in B cells are not known. Here we show that MEF2C enhances the expression of DNA repair and recombination factors in B-cell progenitors, promoting DSB repair, V(D)J recombination and cell survival. Although Mef2c-deficient mice maintain relatively intact peripheral B-lymphoid cellularity during homeostasis, they exhibit poor B-lymphoid recovery after sub-lethal irradiation and 5-fluorouracil injection. MEF2C binds active regulatory regions with high-chromatin accessibility in DNA repair and V(D)J genes in both mouse B-cell progenitors and human B lymphoblasts. Loss of Mef2c in pre-B cells reduces chromatin accessibility in multiple regulatory regions of the MEF2C-activated genes. MEF2C therefore protects B lymphopoiesis during stress by ensuring proper expression of genes that encode DNA repair and B-cell factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cell Survival / radiation effects
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded*
  • Female
  • Fluorouracil / pharmacology
  • Hematopoiesis / drug effects
  • Hematopoiesis / physiology*
  • Hematopoiesis / radiation effects
  • MEF2 Transcription Factors / physiology
  • Male
  • Mice
  • Precursor Cells, B-Lymphoid / drug effects
  • Precursor Cells, B-Lymphoid / physiology*
  • Precursor Cells, B-Lymphoid / radiation effects
  • V(D)J Recombination / physiology*
  • Whole-Body Irradiation / adverse effects

Substances

  • Chromatin
  • MEF2 Transcription Factors
  • Mef2c protein, mouse
  • Fluorouracil