Ten-eleven translocation 2 demethylates the MMP9 promoter, and its down-regulation in preeclampsia impairs trophoblast migration and invasion.
Abstract
Preeclampsia is the most common clinical disorder in pregnancy and might result from disordered uterine environments caused by epigenetic modifications, including deregulation of DNA methylation/demethylation. Recent research has indicated that 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (TET) enzymes, is involved in DNA methylation-related plasticity. Here, we report that TET2 expression and 5hmC abundance are significantly altered in the placentas from preeclampsia patients. shRNA-mediated TET2 knockdown (shTET2) reduced trophoblast migration and invasion when cultured in Matrigel. Both real-time PCR of matrix metalloproteinase (MMP)-related transcripts and a human angiogenesis antibody array indicated that TET2 knockdown in trophoblasts inhibits the expression of MMP transcript, of which MMP9 represented one of the most significant TET2 downstream targets. Using an established shTET2 HTR-8/SVneo cell model, we further confirmed alterations of 5hmC levels and MMP9 expression at both mRNA and protein levels. In particular, we found that TET2 bound to and removed 5mC modifications at the MMP9 promoter region. Interestingly, in TET2 knockdown cells, bot...Continue Reading
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