MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis

• DOI: 10.1038/ncomms12376
• Publication Date: 2016-08-10T09:57:47Z
• Authors: Wenyuan Wang; Tonis Org; Amélie Montel-Hagen; Peter D. Pioli; Dan Duan; Edo Israely; Daniel Malkin; Trent Su; Johanna Flach; Siavash K. Kurdis...; Robert H. Schiestl; Hanna K. A. Mikkola
• Keywords: Male; 0301 basic medicine; Precursor Cells; Cell Survival; 1.1 Normal biological development and functioning; Science; Clinical Sciences; Article; Double-Stranded; Mice; 03 medical and health sciences; Underpinning research; Genetics; 2.1 Biological and endogenous factors; Animals; DNA Breaks, Double-Stranded; Aetiology; Cancer; B-Lymphoid; 0303 health sciences; 5.2 Cellular and gene therapies; Biomedical and Clinical Sciences; MEF2 Transcription Factors; Precursor Cells, B-Lymphoid; DNA Breaks; Q; Stem Cell Research; Chromatin; V(D)J Recombination; Hematopoiesis; 3. Good health; Stem Cell Research - Nonembryonic - Non-Human; Female; Generic health relevance; Fluorouracil; Development of treatments and therapeutic interventions; Whole-Body Irradiation; Biotechnology

AbstractDNA 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.