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

摘要

Summary Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10- null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect 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 embryonic stem cells. Mechanistically, Naa10p facilitates binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates, including the ICRs of the imprinted allele during S phase. Moreover, the lethal Ogden syndrome-associated mutation of human Naa10p disrupts its binding to the ICR of H19 and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated Ogden syndrome to defective DNA methylation and genomic imprinting. Graphical Abstract Display Omitted Highlights ? Naa10p KO causes defects in genomic imprinting and embryonic development ? Naa10p maintains Dnmt1 activity by facilitating Dnmt1 binding to DNA substrate ? Naa10p selectively binds to ICRs of the imprinted allele via non-methylated GCXGXG ? Ogden syndrome-causing Naa10p mutation disrupts ICR binding of Naa10p and Dnmt1 Lee et?al. reveal an unexpected function for Naa10p, which is primarily known to acetylate nascent peptides from ribosomes, in maintaining global DNA methylation and marking the imprinted allele for genomic imprinting maintenance. Their results suggest that defects in DNA methylation and genomic imprinting may contribute to Naa10p-associated Ogden syndrome.