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.
Highlights
DNA double strand break (DSB) repair is critical for generation of B-cell receptors, which are pre-requisite for B-cell progenitor survival
This question is intriguing as Mef2c-deficient mice share features of B-lymphoid ageing[28], which is characterized by reduction of bone marrow B-cell progenitors, whereas peripheral B-cell cellularity can initially be maintained through compensatory mechanisms[11,12,13]
To define the processes that myocyte enhancer factor 2C (MEF2C) regulates in B-lymphoid cells, Mef2cfl/fl was conditionally deleted in mice using Vav-Cre[28,31]
Summary
DNA double strand break (DSB) repair is critical for generation of B-cell receptors, which are pre-requisite for B-cell progenitor survival. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis showed that MEF2C directly binds to several pre-B-cell genes, and possibly regulates them together with other B-cell regulators such as E2A and IKAROS30 These studies show a requirement for MEF2C in B-lymphoid progenitors, the cellular and molecular mechanisms through which MEF2C protects bone marrow B lymphopoiesis are mostly unknown. Little is known about MEF2C function during stress This question is intriguing as Mef2c-deficient mice share features of B-lymphoid ageing[28], which is characterized by reduction of bone marrow B-cell progenitors, whereas peripheral B-cell cellularity can initially be maintained through compensatory mechanisms[11,12,13]
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