How has the Study of the Human Placenta Aided Our Understanding of Partially Methylated Genes?

Abstract

While the human genome sequence is relatively uniform between the cells of an individual, the DNA methylation of the genome (methylome) has unique features in different cells, tissues and stages of development. Recent genome-wide sequencing of the methylome has revealed large partially methylated domains (PMDs) in the human placenta. Unlike CpG islands and Polycomb-regulated regions, which can also have low levels of methylation, placental PMDs cover approximately 37% of the human genome and are associated with inaccessible chromatin and the repression of tissue-specific genes. Here, we summarize the interesting biological questions that have arisen as a result of finding PMDs in the human placenta, including how PMDs form, what they do, how they evolved and how they might be relevant to human disease.

Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting

“…Those regions fulfilling our criteria of partially methylation and hypermethylated in other tissues may simply reflect the relatively hypomethylated nature of the placenta genome that had previously hindered us from performing imprinted DMR analyses in placenta methyl-seq datasets [10]. Recently, Schroeder and colleagues described that the placenta genome has unique partially methylated domains (PMDs) that are larger (>100 kb) and have lower levels of DNA methylation than the rest of the genome, which are stable throughout gestation [21, 36]. The placenta-specific gDMRs we describe are much smaller than PMDs having an average size of 2.2 kb with only two ( CACNA1I and ZNF385D ) mapping to PMDs.…”

The Human Placental Methylome

“…These are large (.100 kb) regions of reduced DNA methylation interspersed with regions of higher DNA methylation . The occurrence of PMDs is unique to placenta, some cultured cells, such as fetal lung fibroblasts, foreskin fibroblasts and adipocytes, and cancer (Lister et al 2011;Schroeder and LaSalle 2013;. Placental PMDs are estimated to cover nearly 40% of the genome and are relatively gene-poor.…”

“…Placental genes within PMDs tend to be tissue-specific, and show higher promoter DNA methylation and reduced expression as compared with somatic tissues . The function of PMDs is unclear, and they have been hypothesized to arise as a consequence of the rapid cell divisions occurring in early placental development or as a programmed mechanism for regulating placental-specific gene expression (Schroeder and LaSalle 2013). If occurring as a result of epigenetic programming, then disruption of such organization could theoretically lead to significant placental dysfunction, including perhaps implantation failure or miscarriage.…”

Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes

“…In oocytes, preimplantation embryos, and placenta, the genome-wide methylation landscape is characterized by the presence of partially methylated domains (PMDs), which are large-scale (>100 kb) regions with <70% CpG methylation (Guo et al., 2014; Schroeder et al, 2013; Schroeder et al, 2011; Schultz et al, 2015; Zhang et al, 2016). PMDs are also observed in all transformed human cell lines that have been examined by whole genome methylation and span genes that are transcriptionally silent in that cell type or tissue (Schroeder and LaSalle, 2013). The occurrence of global hypomethylation over PMDs in placenta and preimplantation embryos compared to brain is conserved across mammals (Schroeder et al, 2015).…”