DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders [ChIP-seq]

Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here we define the effects of neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders. Overall design: Total ChIP-seq from the brains of DNMT3A heterozygous KO and WT mice

DNA甲基转移酶3A（DNMT3A）的突变已在自闭症及相关神经发育障碍中被检出，但此类突变如何扰乱神经系统功能的机制仍未明确。本研究明确了神经发育疾病相关DNMT3A突变的致病效应。我们发现，不同类型的DNMT3A突变会影响蛋白质活性的不同方面，却均会引发神经元DNA甲基化的共性缺陷。模拟疾病状态下DNMT3A功能紊乱的杂合DNMT3A基因敲除小鼠，出现了与人类表型相符的生长与行为异常。尤为值得关注的是，在该类小鼠中，我们检测到神经元富集的非CG型DNA甲基化发生整体紊乱——此类甲基化正是雷特综合征蛋白MeCP2的结合位点。该甲基化的缺失会引发增强子与基因表达失调，其特征与雷特综合征及自闭症模型的表现高度重叠。本研究明确了DNMT3A单倍剂量不足在大脑中的致病效应，并揭示非CG型甲基化通路的紊乱是多种神经发育障碍的共同交汇点。实验设计：对杂合DNMT3A基因敲除（KO）与野生型（WT）小鼠的脑组织开展全染色质免疫共沉淀测序（ChIP-seq）。