Past Issue

Volume 9, Supplement 1, Summer 2015 (Presented at 16th Congress on Reproductive Biomedicine and 10th Royan Nursing and Midwifery Seminar) Pages: 29-29

O-11: N-a-acetyltransferase 10 Protein Regulates DNA Methylation and Embryonic Development

Genomic imprinting is a heritable and developmentally essential phenomenon by which gene expression occurs in an allele-specific manner1. While the imprinted alleles are primarily silenced by DNA methylation, it remains largely unknown how methylation is targeted to imprinting control region (ICR), also called differentially methylated region (DMR), and maintained. Here we show that the Na- acetyltransferase 10 protein (Naa10p), whose mutation is associated with human Ogden syndrome and severe nonsyndromic developmentaldelay, was required for mouse early embryonic development and genomic imprinting.
Materials and methods
Naa10-null mice were generated for analysis of Naa10p effect on DNA methylation and embryonic development. Cell-based genome-wide studies, molecular biology assays such as chromatin immunoprecipitation and bisulfite sequencing, and in vitro gel shift assay were applied.
Naa10-null mice showed partial embryonic lethality, growth retardation, brain disorder and maternal-effect lethality, phenotypes commonly observed in imprinting defects. Consistently, the DNA methylation level of the paternally imprinted alleles of H19-ICR and Rasgrf1-DMR was significantlyreduced in Naa10-KO embryos and ES cells. RNA-seq revealed dysregulation of multiple paternally and maternally imprinted genes that correlate with their DNA methylation alteration. Mechanistically, Naa10p facilitates DNA methyltransferase 1 (Dnmt1) binding to specific imprinted alleles by colocolizing with Dnmt1 in specific imprinting control loci. Moreover, Naa10p associates with the imprinted alleles in vivo independently of Dnmt1. Wild-type Naa10p but not the S37P mutant found in the Ogden syndrome directly bound to H19-ICR and increased DNMT1 binding in vitro
Taken together, our data not only uncover a novel function ofNaa10p in imprinting gene regulation by recruiting DNA methyltransferase 1 but also links imprinting defects to the Ogden syndrome.