Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT 59101, USA.
Computational Biology & Genomics Core (CBGC), Laboratory of Genetics and Genomics (LGG), Department of Health and Human Services (DHHS), National Institute on Aging, Intramural Research Program (NIA IRP), National Institutes of Health (NIH), Biomedical Research Center, Baltimore, MD 21224, USA.
Biol Open. 2021 Sep 15;10(9). doi: 10.1242/bio.058979. Epub 2021 Sep 30.
Elongator dysfunction is increasingly recognized as a contributor to multiple neurodevelopmental and neurodegenerative disorders including familial dysautonomia, intellectual disability, amyotrophic lateral sclerosis, and autism spectrum disorder. Although numerous cellular processes are perturbed in the context of Elongator loss, converging evidence from multiple studies has resolved Elongator's primary function in the cell to the modification of tRNA wobble uridines and the translational regulation of codon-biased genes. Here we characterize H2a.z, encoding the variant H2a histone H2A.Z, as an indirect Elongator target. We further show that canonical Notch signaling, a pathway directed by H2A.Z, is perturbed as a consequence of Elp1 loss. Finally, we demonstrate that hyperacetylation of H2A.Z and other histones via exposure to the histone deacetylase inhibitor Trichostatin A during neurogenesis corrects the expression of Notch3 and rescues the development of sensory neurons in embryos lacking the Elp1 Elongator subunit.
延伸因子功能障碍越来越多地被认为是多种神经发育和神经退行性疾病的病因，包括家族性自主神经异常、智力障碍、肌萎缩侧索硬化症和自闭症谱系障碍。尽管在延伸因子缺失的情况下，许多细胞过程都受到干扰，但来自多个研究的综合证据已经确定延伸因子在细胞中的主要功能是修饰 tRNA 摆动尿嘧啶和翻译调控密码子偏好基因。在这里，我们将编码变体组蛋白 H2A.Z 的 H2a.z 鉴定为间接延伸因子靶标。我们进一步表明，作为 H2A.Z 指导的途径，经典的 Notch 信号通路会因 Elp1 缺失而受到干扰。最后，我们证明，通过在神经发生期间暴露于组蛋白去乙酰化酶抑制剂 Trichostatin A 使 H2A.Z 和其他组蛋白发生超乙酰化，可以纠正 Notch3 的表达，并挽救缺乏 Elp1 延伸因子亚基的胚胎中感觉神经元的发育。
