PGC7 Regulates Genome-Wide DNA Methylation by Regulating ERK-Mediated Subcellular Localization of DNMT1.
PGC7 Regulates Genome-Wide DNA Methylation by Regulating ERK-Mediated Subcellular Localization of DNMT1.
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PGC7 通过调节 ERK 介导的 DNMT1 亚细胞定位来调节全基因组 DNA 甲基化
DOI：
10.3390/ijms24043093
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发表时间：
2023-02-04
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
DNA甲基化是一种表观遗传修饰，在多种生物过程中起着至关重要的作用，包括基因表达、细胞分化、早期胚胎发育、基因组印记和X染色体失活的调控。PGC7是维持早期胚胎发育过程中DNA甲基化的母体因子。通过分析PGC7与UHRF1、H3K9 me2或TET2/TET3之间的相互作用，发现了一种作用机制，揭示了PGC7如何调节卵母细胞或受精胚胎的DNA甲基化。然而，PGC7调控甲基化相关酶翻译后修饰的机制仍有待阐明。这项研究的重点是F9细胞（胚胎癌细胞），显示高水平的PGC7表达。我们发现Pgc7的敲低和ERK活性的抑制都会导致全基因组DNA甲基化水平的增加。机制实验证实，抑制ERK活性导致DNMT1在细胞核中积累，ERK使DNMT1的ser717位点磷酸化，DNMT1 ser717 - ala突变促进DNMT1的核定位。此外，Pgc7的敲低也导致ERK磷酸化下调，促进DNMT1在细胞核内的积累。总之，我们揭示了PGC7通过ERK磷酸化DNMT1 ser717位点调控全基因组DNA甲基化的新机制。这些发现可能为DNA甲基化相关疾病的治疗提供新的见解。
DNA methylation is an epigenetic modification that plays a vital role in a variety of biological processes, including the regulation of gene expression, cell differentiation, early embryonic development, genomic imprinting, and X chromosome inactivation. PGC7 is a maternal factor that maintains DNA methylation during early embryonic development. One mechanism of action has been identified by analyzing the interactions between PGC7 and UHRF1, H3K9 me2, or TET2/TET3, which reveals how PGC7 regulates DNA methylation in oocytes or fertilized embryos. However, the mechanism by which PGC7 regulates the post-translational modification of methylation-related enzymes remains to be elucidated. This study focused on F9 cells (embryonic cancer cells), which display high levels of PGC7 expression. We found that both knockdown of Pgc7 and inhibition of ERK activity resulted in increased genome-wide DNA methylation levels. Mechanistic experiments confirmed that inhibition of ERK activity led to the accumulation of DNMT1 in the nucleus, ERK phosphorylated DNMT1 at ser717, and DNMT1 Ser717-Ala mutation promoted the nuclear localization of DNMT1. Moreover, knockdown of Pgc7 also caused downregulation of ERK phosphorylation and promoted the accumulation of DNMT1 in the nucleus. In conclusion, we reveal a new mechanism by which PGC7 regulates genome-wide DNA methylation via phosphorylation of DNMT1 at ser717 by ERK. These findings may provide new insights into treatments for DNA methylation-related diseases.
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影响因子：
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作者：
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