Department of Zoology, Life Sciences Institute and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Mol Cell Neurosci. 2010 May;44(1):55-67. doi: 10.1016/j.mcn.2010.02.003. Epub 2010 Feb 24.
DNA methylation-dependent gene silencing is initiated by DNA methyltransferases (DNMTs) and mediated by methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs) to silence DNA, a process that is essential for normal development. Here, we show that the MBD proteins MBD2 and MeCP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation in vivo. Mbd2 null progenitors display enhanced proliferation, recapitulated by HDAC inhibition, and Mbd2 null ORNs have a decreased lifespan. Mecp2 null ORNs, on the other hand, temporarily stall at the stage of terminal differentiation, retaining expression of the immature neuronal protein GAP43 after initiating expression of mature neuronal genes. The Gap43 promoter is highly methylated in the mature, but not embryonic olfactory epithelium (OE), suggesting that Gap43 may be regulated by DNA methylation during ORN differentiation. Thus, MBD2 and MeCP2 may mediate distinct, sequential transitions of ORN differentiation-an epigenetic mechanism that may be relevant to developmental regulation throughout the nervous system.
DNA 甲基化依赖性基因沉默是由 DNA 甲基转移酶 (DNMTs) 启动的，并由甲基结合域蛋白 (MBDs) 介导，后者招募组蛋白去乙酰化酶 (HDACs) 来沉默 DNA，这一过程对于正常发育至关重要。在这里，我们表明 MBD 蛋白 MBD2 和 MeCP2 在体内调节嗅觉受体神经元 (ORN) 分化的不同过渡阶段。Mbd2 缺失祖细胞表现出增强的增殖，这可被 HDAC 抑制所再现，并且 Mbd2 缺失的 ORN 寿命缩短。另一方面，Mecp2 缺失的 ORN 暂时停滞在终末分化阶段，在起始表达成熟神经元基因后保留不成熟神经元蛋白 GAP43 的表达。Gap43 启动子在成熟但不在胚胎嗅上皮 (OE) 中高度甲基化，这表明 Gap43 可能在 ORN 分化过程中受 DNA 甲基化调控。因此，MBD2 和 MeCP2 可能介导 ORN 分化的不同、连续的过渡——这一表观遗传机制可能与整个神经系统的发育调控有关。
