DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation

Abstract

BackgroundGenomic imprinting is an epigenetically regulated process wherein genes are expressed in a parent-of-origin specific manner. Many imprinted genes were initially identified in mice; some of these were subsequently shown not to be imprinted in humans. Such discrepancy reflects developmental, morphological and physiological differences between mouse and human tissues. This is particularly relevant for the placenta. Study of genomic imprinting thus needs to be carried out in a species and developmental stage-specific manner. We describe here a new strategy to study allele-specific DNA methylation in the human placenta for the discovery of novel imprinted genes.ResultsUsing this methodology, we confirmed 16 differentially methylated regions (DMRs) associated with known imprinted genes. We chose 28 genomic regions for further testing and identified two imprinted genes (DNMT1 and AIM1). Both genes showed maternal allele-specific methylation and paternal allele-specific transcription. Imprinted expression for AIM1 was conserved in the cynomolgus macaque placenta, but not in other macaque tissues or in the mouse.ConclusionsOur study indicates that while there are many genomic regions with allele-specific methylation in tissues like the placenta, only a small sub-set of them are associated with allele-specific transcription, suggesting alternative functions for such genomic regions. Nonetheless, novel tissue-specific imprinted genes remain to be discovered in humans. Their identification may help us better understand embryonic and fetal development.

Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta

“…In addition, we corroborated the imprinted regulation of recently established AIM1 19 , and RHOBTB3 11 . For all these genes, we were able to identify one (PEG10) or 3-4 (RHOBTB3 and AIM1, respectively) phased SNPs for showing the parental specific expression of the genes among the 10 families studied (Fig.…”

Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment

“…All new regions of ubiquitous imprinted methylation identified in the current screen are associated predominantly with type II Infinium probes and were not present on previous array platforms. Of the placental-specific DMRs, only those associated with DNMT1, AIM1, and MCCC1 have been previously described (Yuen et al 2011;Das et al 2013). Intriguingly, the somatic promoter of Dnmt1 is differentially methylated between sperm and oocytes but is lost during preimplantation development (Smallwood et al 2011;Kobayashi et al 2012).…”

The Human Placental Methylome

“…Cite this article as Cold Spring Harb Perspect Med 2015;5:a023044 methyltransferase gene DNMT1 shows placental-specific imprinting with maternal-allele DNA methylation and paternal-allele expression in the placenta (Das et al 2013). Some imprinted genes, such as CDKN1C and IGF2, have placental-specific promoters (Monk et al 2006;Yuen et al 2011a), illustrating that placental imprinted differentially methylated regions (DMRs) may differ from somatic ones for a given imprinted gene.…”