Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Institute for Advanced Study, Tongji University, Shanghai, China.
EMBO Rep. 2020 Nov 5;21(11):e50283. doi: 10.15252/embr.202050283. Epub 2020 Oct 5.
A microdeletion within human chromosome 5q14.3 has been associated with the occurrence of neurodevelopmental disorders, such as autism and intellectual disability, and MEF2C haploinsufficiency was identified as main cause. Here, we report that a brain-enriched long non-coding RNA, NDIME, is located near the MEF2C locus and is required for normal neural differentiation of mouse embryonic stem cells (mESCs). NDIME interacts with EZH2, the major component of polycomb repressive complex 2 (PRC2), and blocks EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) at the Mef2c promoter, promoting MEF2C transcription. Moreover, the expression levels of both NDIME and MEF2C were strongly downregulated in the hippocampus of a mouse model of autism, and the adeno-associated virus (AAV)-mediated expression of NDIME in the hippocampus of these mice significantly increased MEF2C expression and ameliorated autism-like behaviors. The results of this study reveal an epigenetic mechanism by which NDIME regulates MEF2C transcription and neural differentiation and suggest potential effects and therapeutic approaches of the NDIME/MEF2C axis in autism.
人类染色体 5q14.3 上的微缺失与神经发育障碍（如自闭症和智力障碍）的发生有关，MEF2C 杂合不足被确定为主要原因。在这里，我们报告说，一种丰富存在于脑中的长非编码 RNA，NDIME，位于 MEF2C 基因座附近，是正常的小鼠胚胎干细胞（mESCs）神经分化所必需的。NDIME 与 EZH2 相互作用，EZH2 是多梳抑制复合物 2（PRC2）的主要组成部分，并阻止 EZH2 介导的 Mef2c 启动子上组蛋白 H3 赖氨酸 27（H3K27me3）的三甲基化，从而促进 MEF2C 转录。此外，自闭症小鼠模型海马体中 NDIME 和 MEF2C 的表达水平均显著下调，而这些小鼠海马体中腺相关病毒（AAV）介导的 NDIME 表达可显著增加 MEF2C 的表达并改善自闭症样行为。这项研究揭示了 NDIME 调节 MEF2C 转录和神经分化的表观遗传机制，并提示 NDIME/MEF2C 轴在自闭症中的潜在作用和治疗方法。
