MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis

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.

MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease

“…In addition, MEF2C is found to be highly expressed in B cells of the spleen and lymph node and plays a critical role in B cell proliferation upon antigen stimulation . Recently, MEF2C was reported to protect B lymphopoiesis during stress by ensuring proper expression of genes that encode DNA repair and B‐cell factors . Interestingly, the non‐competitive N ‐methyl‐ d ‐aspartate receptor antagonist, memantine, also attenuates adaptive as well as innate B cell signaling and may be useful to target B cells under pathological inflammatory conditions like AD .…”

“…MEF2C is also reported to be a central transcriptional component of the innate immune response . In the adult human brain, MEF2C is highly expressed in brain regions involved in learning and memory, such as the frontal cortex, entorhinal cortex, dentate gyrus, and amygdala . Thus, it is plausible that MEF2C is also involved in the inflammatory process in the brains of AD through regulating microglia proliferation .…”

“…14,44 Recently, MEF2C was reported to protect B lymphopoiesis during stress by ensuring proper expression of genes that encode DNA repair and B-cell factors. 15 Interestingly, the noncompetitive N-methyl-D-aspartate receptor antagonist, memantine, also attenuates adaptive as well as innate B cell signaling and may be useful to target B cells under pathological inflammatory conditions like AD. 16 MEF2C is also reported to be a central transcriptional component of the innate immune response.…”

“…MEF2C is involved in inflammatory processes and plays a critical role in B‐cell proliferation upon antigen stimulation, which occurs following foreign antigen binding to B cell receptors . MEF2C enhances the expression of DNA repair molecules and recombination factors in B‐cell progenitors and promotes cell survival . A non‐competitive N ‐methyl‐ d ‐aspartate receptor antagonist, memantine, reduces B‐cell proliferation and is used to treat the symptoms of AD.…”

“…14 MEF2C enhances the expression of DNA repair molecules and recombination factors in B-cell progenitors and promotes cell survival. 15 A non-competitive N-methyl-D-aspartate receptor antagonist, memantine, reduces B-cell proliferation 16 and is used to treat the symptoms of AD. These data suggest the presence of a relation between B cell immunological responses and AD.…”