Ritchie Foster D, Lizarraga Sofia B
Department of Biological Sciences and Center for Childhood Neurotherapeutics, University of South Carolina, Columbia, SC, United States.
Front Neurosci. 2023 Feb 10;17:989109. doi: 10.3389/fnins.2023.989109. eCollection 2023.
Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.
在神经元发育过程中，脑容量受多种因素控制，包括神经祖细胞增殖、神经元分支形成、神经胶质细胞生成、细胞死亡和突触形成。多种神经发育障碍伴有脑容量异常，如小头畸形和巨头畸形。在涉及小头畸形和巨头畸形的神经发育障碍中，已发现可修饰组蛋白H3赖氨酸36和赖氨酸4（H3K36和H3K4）的组蛋白甲基转移酶发生突变。H3K36和H3K4甲基化均与转录激活相关，并被认为在空间上阻碍了多梳抑制复合物2（PRC2）的抑制活性。在神经元发育过程中，PRC2介导的H3K27三甲基化（H3K27me3）导致调控细胞命运转变和神经元分支形成的基因在全基因组范围内发生转录抑制。在此，我们综述了与H3K36和H3K4组蛋白甲基转移酶相关的神经发育过程和障碍，重点关注导致脑容量异常的过程。此外，我们还讨论了H3K36和H3K4修饰酶与PRC2的拮抗作用如何导致脑容量异常，这是一种在脑容量控制方面尚未充分探索的机制。
