PGC7 Regulates Genome-Wide DNA Methylation by Regulating ERK-Mediated Subcellular Localization of DNMT1.

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.

[Abnormalities of microsatellite in transitional cell carcinoma of urinary bladder related with aromatic amine exposure].

OBJECTIVE: To study the microsatellite abnormalities of the aromatic amine exposure-associated transitional cell carcinoma (TCC) and sporadic TCC of urinary bladder, and to evaluate the potential of microsatellite analysis on detection of this diseases. METHODS: Based on our previous investigations, 5 microsatellite markers (D17S695, D9S162, D3S1295, DBH and D3S1234) that had high frequencies of loss of heterozygosity (LOH) in sporadic TCC, were selected for analysis with the bladder lesions derived from 16 patients with aromatic amine exposure history. The microsatellite analysis with urine sediments from the post-operated patients was also carried out. RESULTS: There was at least one informative marker out of the 5 microsatellite foci showed polymorphism in the DNA derived from 16 patients examined. Within 87.50% (14/16) patients, LOH was detected in the bladder lesions at least with one microsatellite marker. The LOH frequency of D3S1295 was higher in occupational TCC patients than that in sporadic TCC patients. The diagnostic accordance rate of patients showed LOH in at least one microsatellite marker with patients diagnosed by pathology was 81.25% (13/16). In the urine sediments from 8 TCC post-operated patients, LOH was found at least with one microsatellite marker. CONCLUSION: There could be a different LOH pattern in aromatic amine exposure-associated TCC, and genes near D3S1295 might play a role in the occupational exposure-associated TCC.