Maternal DNA Methylation Regulates Early Trophoblast Development

Abstract

SummaryCritical roles for DNA methylation in embryonic development are well established, but less is known about its roles during trophoblast development, the extraembryonic lineage that gives rise to the placenta. We dissected the role of DNA methylation in trophoblast development by performing mRNA and DNA methylation profiling of Dnmt3a/3b mutants. We find that oocyte-derived methylation plays a major role in regulating trophoblast development but that imprinting of the key placental regulator Ascl2 is only partially responsible for these effects. We have identified several methylation-regulated genes associated with trophoblast differentiation that are involved in cell adhesion and migration, potentially affecting trophoblast invasion. Specifically, trophoblast-specific DNA methylation is linked to the silencing of Scml2, a Polycomb Repressive Complex 1 protein that drives loss of cell adhesion in methylation-deficient trophoblast. Our results reveal that maternal DNA methylation controls multiple differentiation-related and physiological processes in trophoblast via both imprinting-dependent and -independent mechanisms.

Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia

“…23,24 In agreement with these results, we found that DNMT3A is necessary for the migration and invasion of trophoblast cells and is dysregulated in PE. In addition, the functions of other DNMTs in embryonic development have also been studied.…”

“…23 Furthermore, it has been proved that maternal deletion of Dnmt3a/b causes the defects of trophoblast development at embryonic day 9.5, which is represented by a deficient labyrinthine layer and a low-density trophoblast giant cell layer, possibly as a result of decreased cell adhesion and migration. 24 However, little is known about the role of DNMT3A in PE.…”

Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors

“…Accordingly, SCML2 plays a role in modulating the cell-cycle machinery and impacts the cellular activity when it is ectopically expressed in transformed or cancer cells (28,29). In addition, there is evidence suggesting that SCML2 may be involved in human tumors, including malignant pediatric brain tumors, acute myeloid leukemia and human hepatocellular carcinoma (30)(31)(32)(33)(34)(35)(36). The above knowledge about SCML2, together with previous findings on SCML2 expression in islet-cell carcinoma (12)(13)(14), inspired the investigation of a more explicit linkage between SCML2 and GEP-NETs, a tumor with an increasing incidence worldwide, in the present study.…”

Deconstructing the winding path to the recapitulation of mammalian oogenesis ex vivo

“…Keep in mind that the processes of growth and transcriptional efficiency, coupled to histone modifications required for the expression of housekeeping and maternal effect gene products (11), involve dynamic histone changes that precede imprinting methylations (12). Moreover, these stage-specific methylation marks of both imprinted and nonimprinted varieties control later developmental events bearing directly on implantation and trophectoderm development (13). Again, the paper by Morohaku et al (1) validates appropriate epigenetic modifications at each stage, then confirms the documented oocytes will give rise to healthy offspring.…”