Abstract
Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte–derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.
Highlights
The process of genomic imprinting establishes and maintains parental alleles in opposing epigenetic states resulting in expression of imprinted genes from just one parental allele
This monoallelic imprinted gene expression is determined by inherited parent-specific DNA methylation patterns at autosomal gametic differentially methylated domains that are perpetuated in the embryo such that one parental allele is methylated and the other is unmethylated
There was a trend toward mutants approaching wild-type levels of imprinted gametic differentially methylated domains (gDMDs) methylation levels as gestation progressed; average gDMD methylation increased from E12.5 to E15.5 (P
Summary
The process of genomic imprinting establishes and maintains parental alleles in opposing epigenetic states resulting in expression of imprinted genes from just one parental allele. This monoallelic imprinted gene expression is determined by inherited parent-specific DNA methylation patterns at autosomal gametic differentially methylated domains (gDMDs) that are perpetuated in the embryo such that one parental allele is methylated and the other is unmethylated. Partial disruption of genomic imprint inheritance during preimplantation, through maternal deletion of DNMT1o, permanently ablates affected gDMD methylation from embryonic and extra-embryonic lineages and directly results in biallelic expression or repression of nearby clusters of imprinted genes [4,5]
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