BRIC, University of Copenhagen, Biotech Research and Innovation Centre, Ole Maaloes vej 5, 2200, Copenhagen, Denmark.
BRIC, University of Copenhagen, Biotech Research and Innovation Centre, Ole Maaloes vej 5, 2200, Copenhagen, Denmark
Development. 2020 Aug 7;147(15):dev190637. doi: 10.1242/dev.190637.
Post-translational histone modifications regulate chromatin compaction and gene expression to control many aspects of development. Mutations in genes encoding regulators of H3K4 methylation are causally associated with neurodevelopmental disorders characterized by intellectual disability and deficits in motor functions. However, it remains unclear how H3K4 methylation influences nervous system development and contributes to the aetiology of disease. Here, we show that the catalytic activity of , the homologue of the H3K4 methyltransferase KMT2F/G (SETD1A/B) genes, controls embryonic transcription of neuronal genes and is required for establishing proper axon guidance, and for neuronal functions related to locomotion and learning. Moreover, we uncover a striking correlation between components of the H3K4 regulatory machinery mutated in neurodevelopmental disorders and the process of axon guidance in Thus, our study supports an epigenetic-based model for the aetiology of neurodevelopmental disorders, based on an aberrant axon guidance process originating from deregulated H3K4 methylation.
翻译后组蛋白修饰调节染色质压缩和基因表达，以控制发育的许多方面。编码H3K4甲基化调节因子的基因突变与以智力残疾和运动功能缺陷为特征的神经发育障碍存在因果关系。然而，H3K4甲基化如何影响神经系统发育并导致疾病病因仍不清楚。在这里，我们表明，H3K4甲基转移酶KMT2F/G（SETD1A/B）基因的同源物的催化活性控制神经元基因的胚胎转录，是建立正确的轴突导向以及与运动和学习相关的神经元功能所必需的。此外，我们发现神经发育障碍中发生突变的H3K4调节机制的成分与轴突导向过程之间存在显著相关性。因此，我们的研究支持了一种基于表观遗传学的神经发育障碍病因模型，该模型基于源自H3K4甲基化失调的异常轴突导向过程。
