MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis.
MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis.
复制标题
MEF2C在应激造血过程中保护骨髓B淋巴祖细胞。
DOI：
10.1038/ncomms12376
复制
发表时间：
2016-08-10
影响因子：
16.6
通讯作者：
Mikkola HK
中科院分区：
文献类型：
--
作者：
Wang W;Org T;Montel-Hagen A;Pioli PD;Duan D;Israely E;Malkin D;Su T;Flach J;Kurdistani SK;Schiestl RH;Mikkola HK
DNA双链断裂（DSB）修复对于B细胞受体的产生至关重要，这是B细胞祖细胞存活的先决条件。然而，促进B细胞中DSB修复的转录因子尚不清楚。在这里，我们表明，MEF 2C增强了B细胞祖细胞中DNA修复和重组因子的表达，促进DSB修复，V（D）J重组和细胞存活。尽管Mef 2c缺陷小鼠在体内平衡过程中保持相对完整的外周B淋巴细胞结构，但在亚致死照射和5-氟尿嘧啶注射后，它们表现出较差的B淋巴恢复。MEF 2C结合小鼠B细胞祖细胞和人B淋巴母细胞中DNA修复和V（D）J基因中具有高染色质可及性的活性调节区。前B细胞中Mef 2c的缺失降低了MEF 2C激活基因的多个调控区域中的染色质可及性。因此，MEF 2 C通过确保编码DNA修复和B细胞因子的基因的正确表达，在应激期间保护B淋巴细胞生成。 MEF 2C是B细胞增殖所需的转录因子。在这里，作者表明MEF 2C也是B细胞发育和从应激中恢复所必需的，通过诱导DNA修复因子的表达来防止双链断裂并使VDJ重组成为可能。
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 is a transcription factor required for B-cell proliferation. Here the authors show that MEF2C is also needed in B-cell development and recovery from stress by inducing expression of DNA repair factors that prevent double stranded breaks and enable VDJ recombination.