加拿大麦吉尔大学Nada Jabado团队发现，H3.3G34的单一替换改变DNMT3A的招募来致使渐进性神经变性。该项研究成果发表在2023年3月16日出版的《细胞》杂志上。
种系组蛋白H3.3氨基酸替换，包括H3.3G34R/V，导致严重的神经发育综合征。为了了解这些突变是如何影响大脑发育的，研究人员产生了H3.3G34R/V/W基因敲入小鼠，并发现每种突变都有明显的发育缺陷。H3.3G34R突变体表现出渐进性小头畸形和神经变性，与疾病相关的小胶质细胞异常聚集，同时出现神经元耗竭。G34R严重降低了突变体H3.3尾部的H3K36me2，并损害了DNA甲基转移酶DNMT3A的招募和它在染色质上的重新分布。这些变化与补体和其他先天免疫基因的持续表达同时发生，可能是通过非CG（CH）甲基化的丧失和通过异常的CG甲基化对神经元基因启动子进行沉默。补体在G34R大脑中的表达可能导致神经炎症，可能是进行性神经退化的原因。
这项研究揭示了H3.3G34替换对表观基因组有不同的影响，这是观察到的不同表型的基础，并发现了H3K36me2和DNMT3A依赖的CH-甲基化在调节产后大脑的突触修剪和神经炎症中的潜在作用。
附：英文原文
Title: Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration
Author: Sima Khazaei, Carol C.L. Chen, Augusto Faria Andrade, Nisha Kabir, Pariya Azarafshar, Shahir M. Morcos, Josiane Alves Frana, Mariana Lopes, Peder J. Lund, Geoffroy Danieau, Samantha Worme, Lata Adnani, Nadine Nzirorera, Xiao Chen, Gayathri Yogarajah, Caterina Russo, Michele Zeinieh, Cassandra J. Wong, Laura Bryant, Steven Hébert, Bethany Tong, Tianna S. Sihota, Damien Faury, Evan Puligandla, Wajih Jawhar, Veronica Sandy, Mitra Cowan, Emily M. Nakada, Loydie A. Jerome-Majewska, Benjamin Ellezam, Carolina Cavalieri Gomes, Jonas Denecke, Davor Lessel, Marie T. McDonald, Carolyn E. Pizoli, Kathryn Taylor, Benjamin T. Cocanougher, Elizabeth J. Bhoj, Anne-Claude Gingras, Benjamin A. Garcia, Chao Lu, Eric I. Campos, Claudia L. Kleinman, Livia Garzia, Nada Jabado
Issue&Volume: 2023/03/16
Abstract: Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severeneurodevelopmental syndromes. To understand how these mutations impact brain development,we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmentaldefects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly andneurodegeneration, with abnormal accumulation of disease-associated microglia andconcurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistributionon chromatin. These changes were concurrent with sustained expression of complementand other innate immune genes possibly through loss of non-CG (CH) methylation andsilencing of neuronal gene promoters through aberrant CG methylation. Complement expressionin G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration.Our study reveals that H3.3G34-substitutions have differential impact on the epigenome,which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammationin post-natal brains.
DOI: 10.1016/j.cell.2023.02.023
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00166-6