Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), of which the underlying mechanism remains largely unclear. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternaleffect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and ES cells. Mechanistically, Naa10p facilitates the binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates and recruits Dnmt1 to ICRs of the imprinted allele during S phase. Moreover, the clinical lethal Ogden syndrome-associated mutation of Naa10p disrupts its binding to H19-ICR and Dnmt1 recruitment. Our study thus links Naa10p mutationassociated human disease to defective DNA methylation and genomic imprinting. Examination of Naa10p binding sites in WT mouse embryonic stem (ES) cells using Naa10-KO ES cells as control

基因组印记（Genomic imprinting）是一种主要由印记控制区（imprinting control region, ICR）处的等位基因特异性DNA甲基化调控的等位基因表达现象，其背后的分子机制目前尚未完全阐明。哺乳动物N-α-乙酰转移酶10蛋白（N-α-acetyltransferase 10 protein, Naa10p）可催化新生蛋白质的N-α乙酰化修饰。人类Naa10p的突变与严重的发育迟缓相关。本研究发现，Naa10基因敲除（Naa10-null）小鼠表现出部分胚胎致死、生长迟缓、脑部发育异常以及母源效应致死表型，此类表型常见于基因组印记缺陷的模型中。全基因组分析进一步显示，在Naa10p敲除（Naa10p-knockout）胚胎与胚胎干细胞（embryonic stem cells, ES cells）中存在全基因组DNA低甲基化，以及印记基因的异常表达富集。机制研究表明，Naa10p可促进DNA甲基转移酶1（DNA methyltransferase 1, Dnmt1）与DNA底物的结合，并在S期将Dnmt1招募至印记等位基因的印记控制区。此外，与临床致死性Ogden综合征相关的Naa10p突变，会破坏其与H19-ICR的结合以及对Dnmt1的招募功能。本研究因此将Naa10p突变相关的人类疾病与DNA甲基化缺陷及基因组印记异常联系起来。以Naa10基因敲除胚胎干细胞（Naa10-KO ES cells）为对照，对野生型（wild type, WT）小鼠胚胎干细胞（mouse embryonic stem cells, ES cells）中的Naa10p结合位点进行检测