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  • Another novel finding of our

    2019-07-10

    Another novel finding of our study was that the global 5 hmC was down-regulated and was associated with a substantial reduction of TET expression in the PE placentas compared with the controls. The decreased global 5 hmC level was consistent with the increased global 5 mC level in the preeclamptic placentas. These data suggest that the DNA methylation status is based on a balance between 5 mC and 5 hmC, and that DNA methylation is reversible in the placenta. As recently shown, increases in the levels of TET2 and TET3 coincided with the increases in 5 hmC in differentiating neurons in the developing mouse Propranolol HCl what cortex [41]. Furthermore, another study has also shown that TET1 promoted active DNA demethylation in the nervous system [42]. Koh et al. suggested that TET1 and TET2 regulated 5 hmC levels and Oct4 regulated TET mRNA levels in mouse embryonic stem cells [19]. Evidence from emerging research has shown that a loss of 5 hmC in different types of tumors was consistent with low TET gene expression in cancer [17], [18]. These studies reiterate our findings in placental tissue. Previous studies have demonstrated that the decreased level of 5 hmC in tumors was a result of the reduced expression of TET1/2/3 and IDH2 genes or tumor derived IDH1 and IDH2 mutations [43], [44]. However, to date, the TET or IDH 1/2 genes have not been reported to be mutated in the placentas of patients who suffer from pregnancy complications. In our research, we determined that the mRNA expression of all three TET genes was significantly reduced in the PE placentas compared with the controls. It is noteworthy that the reduction of the three TET genes varied, and TET3 mRNA expression was reduced most significantly, followed by TET2 and TET1. Furthermore, TET1 and TET3 protein expression clearly diminished in the preeclamptic placentas. These data indicate that TET1/3 may play an important role in the conversion of 5 mC to 5 hmC in the placenta. In addition, Xu et al. implied that TET1 strongly bind to the promoter of YWHAQ in ChIP-Seq analysis in mouse embryonic stem cell [23]. The data presented here speak of a possible correlation between TET and methylation/hydrocymethylation of YWHAQ. Further analysis is required to determine the exact cause of and potential molecular mechanism for the changes in TET expression in preeclamptic placentas.
    Conflict of interest
    Intracellular folates are required as cofactors in DNA synthesis, repair, and methylation, and they are essential for normal cellular growth and replication., Antifolates, such as methotrexate (MTX), are competitive inhibitors of folate-dependent enzymes and are widely used in the treatment of many human cancers, including acute lymphoblastic leukemia (ALL). Folates and most antifolates exist intracellularly as more-active polyglutamated derivatives, which are retained longer in cells because they are generally not substrates of export transporters. Hydrolytic removal of γ-linked polyglutamates, including folylpoly-γ-glutamates and antifolylpoly-γ-glutamates, is catalyzed by the lysosomal peptidase γ-glutamyl hydrolase (GGH [MIM ]). MTX is a major component of the curative treatment of childhood ALL, and the extent of accumulation of its active polyglutamates (MTXPG) determines its cytotoxicity and influences treatment response in childhood ALL. GGH converts long-chain MTXPG into shorter-chain MTXPG and ultimately into MTX, which can be effluxed from cells., In children with nonhyperdiploid B-lineage ALL (BNHD-ALL), GGH activity in leukemia cells is inversely correlated with long-chain MTXPG accumulation. Hyperdiploid B-lineage ALL (BHD-ALL) cells with trisomy of chromosome 8 that contains a wild-type allele have significantly higher GGH activity and accumulate less MTXPG than do those with disomy 8. GGH activity and MTXPG accumulation in leukemia cells are also affected by a substrate-specific functional genetic polymorphism in , 452C→T (T127I, ). This SNP alters GGH\'s surface conformation at the substrate-binding cleft and reduces its binding affinity to long-chain MTXPG. Among patients with the same ALL subtype (e.g., BNHD-ALL, T-lineage ALL, or BHD-ALL without an additional chromosome 8), 452C→T was found at high frequency among patients with low GGH activity, and it was not found in patients with high GGH activity. However, there remains substantial interindividual variability in GGH activity that is not explained by genetic polymorphism or karyotypic abnormalities.