NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons.
NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons.
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DOI：
10.1016/j.molcel.2023.04.001
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发表时间：
2023-04
期刊：
影响因子：
16
通讯作者：
Nicole Hamagami;Dennis Y. Wu;Adam W. Clemens;Sabin A. Nettles;Aidan Li;Harrison W. Gabel
中科院分区：
文献类型：
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作者：
Nicole Hamagami;Dennis Y. Wu;Adam W. Clemens;Sabin A. Nettles;Aidan Li;Harrison W. Gabel
在出生后发育期间，DNA甲基转移酶DNMT 3A在神经元中沉积高水平的非CG胞嘧啶甲基化。这种甲基化对于转录调控至关重要，并且这种标记的丢失与DNMT 3A相关的神经发育障碍（NDD）有关。在这里，我们在小鼠中显示，基因组拓扑结构和基因表达收敛于形成组蛋白H3赖氨酸36二甲基化（H3 K36 me 2）谱，这反过来又招募DNMT 3A和模式神经元非CG甲基化。我们发现，NSD 1，一个H3 K36甲基转移酶突变的NDD，是所需的兆碱基规模的H3 K36 me 2和非CG甲基化在神经元中的图案。我们发现，NSD 1的脑特异性缺失导致DNA甲基化改变，与DNMT 3A疾病模型重叠，以驱动关键神经元基因的会聚失调，这些基因可能是NSD 1和DNMT 3A相关NDD中共享表型的基础。我们的研究结果表明，NSD 1沉积的H3 K36 me 2对神经元非CG DNA甲基化很重要，并表明H3 K36 me 2-DNMT 3A-非CG-甲基化途径可能在NSD 1相关的NDD中被破坏。
During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, an H3K36 methyltransferase mutated in NDD, is required for the patterning of megabase-scale H3K36me2 and non-CG methylation in neurons. We find that brain-specific deletion of NSD1 causes altered DNA methylation that overlaps with DNMT3A disorder models to drive convergent dysregulation of key neuronal genes that may underlie shared phenotypes in NSD1- and DNMT3A-associated NDDs. Our findings indicate that H3K36me2 deposited by NSD1 is important for neuronal non-CG DNA methylation and suggest that the H3K36me2-DNMT3A-non-CG-methylation pathway is likely disrupted in NSD1-associated NDDs.