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Structural and regulatory characterization of the placental epigenome at its maternal interface.

Chu T, Handley D, Bunce K, Surti U, Hogge WA, Peters DG - PLoS ONE (2011)

Bottom Line: One setting in which epigenetics is likely to have a profound influence on biological phenotype is during intrauterine development.Furthermore, we found that these relationships were significantly associated with CpG content.We conclude that the early gestational placental DNA methylome is highly organized and is significantly and globally associated with transcription.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Epigenetics can be loosely defined as the study of cellular "traits" that influence biological phenotype in a fashion that is not dependent on the underlying primary DNA sequence. One setting in which epigenetics is likely to have a profound influence on biological phenotype is during intrauterine development. In this context there is a defined and critical window during which balanced homeostasis is essential for normal fetal growth and development. We have carried out a detailed structural and functional analysis of the placental epigenome at its maternal interface. Specifically, we performed genome wide analysis of DNA methylation in samples of chorionic villus (CVS) and maternal blood cells (MBC) using both commercially available and custom designed microarrays. We then compared these data with genome wide transcription data for the same tissues. In addition to the discovery that CVS genomes are significantly more hypomethylated than their MBC counterparts, we identified numerous tissue-specific differentially methylated regions (T-DMRs). We further discovered that these T-DMRs are clustered spatially along the genome and are enriched for genes with tissue-specific biological functions. We identified unique patterns of DNA methylation associated with distinct genomic structures such as gene bodies, promoters and CpG islands and identified both direct and inverse relationships between DNA methylation levels and gene expression levels in gene bodies and promoters respectively. Furthermore, we found that these relationships were significantly associated with CpG content. We conclude that the early gestational placental DNA methylome is highly organized and is significantly and globally associated with transcription. These data provide a unique insight into the structural and regulatory characteristics of the placental epigenome at its maternal interface and will drive future analyses of the role of placental dysfunction in gestational disease.

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Scatter plot of genome-wide DNA methylation levels (Beta) of CVS and MBC genomes based on the Infinium data.
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pone-0014723-g001: Scatter plot of genome-wide DNA methylation levels (Beta) of CVS and MBC genomes based on the Infinium data.

Mentions: We identified five fold more T-DMRs that were hypomethylated in CVS versus MBC compared to those that were hypomethylated in MBC versus CVS (Figure 1). This does not appear to be an artifact since we observed the same phenomenon in both the Agilent and Illumina data sets and each of these approaches relies upon significantly different library preparation methods. Furthermore, when we plotted the frequency of methylation at specific CpG sites in MBCs using the Illumina data we found there to be a clear bimodal distribution, with large numbers of CpG sites that are either completely hypermethylated or completely hypomethylated (Figure 2A). This bimodal pattern was also evident for a variety of cell lines (Figure 2B) and primary ovarian tumor samples (Figure 2C). These samples were used for comparison because they serve as examples of both cultured and uncultured transformed cell tissue types respectively. We chose neoplastic samples for this purpose because of the previously suggested similarities between the molecular phenotype of placental tissues and tumors [25]. Data from cell lines were obtained directly from Illumina whereas the primary ovarian tumor data were obtained in our own lab as part of a separate experiment. The bimodal distribution was, however, not evident in CVS genomes, which displayed significantly fewer fully hypermethylated sites and significantly more partially methylated sites (Figure 2D).


Structural and regulatory characterization of the placental epigenome at its maternal interface.

Chu T, Handley D, Bunce K, Surti U, Hogge WA, Peters DG - PLoS ONE (2011)

Scatter plot of genome-wide DNA methylation levels (Beta) of CVS and MBC genomes based on the Infinium data.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044138&req=5

pone-0014723-g001: Scatter plot of genome-wide DNA methylation levels (Beta) of CVS and MBC genomes based on the Infinium data.
Mentions: We identified five fold more T-DMRs that were hypomethylated in CVS versus MBC compared to those that were hypomethylated in MBC versus CVS (Figure 1). This does not appear to be an artifact since we observed the same phenomenon in both the Agilent and Illumina data sets and each of these approaches relies upon significantly different library preparation methods. Furthermore, when we plotted the frequency of methylation at specific CpG sites in MBCs using the Illumina data we found there to be a clear bimodal distribution, with large numbers of CpG sites that are either completely hypermethylated or completely hypomethylated (Figure 2A). This bimodal pattern was also evident for a variety of cell lines (Figure 2B) and primary ovarian tumor samples (Figure 2C). These samples were used for comparison because they serve as examples of both cultured and uncultured transformed cell tissue types respectively. We chose neoplastic samples for this purpose because of the previously suggested similarities between the molecular phenotype of placental tissues and tumors [25]. Data from cell lines were obtained directly from Illumina whereas the primary ovarian tumor data were obtained in our own lab as part of a separate experiment. The bimodal distribution was, however, not evident in CVS genomes, which displayed significantly fewer fully hypermethylated sites and significantly more partially methylated sites (Figure 2D).

Bottom Line: One setting in which epigenetics is likely to have a profound influence on biological phenotype is during intrauterine development.Furthermore, we found that these relationships were significantly associated with CpG content.We conclude that the early gestational placental DNA methylome is highly organized and is significantly and globally associated with transcription.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Epigenetics can be loosely defined as the study of cellular "traits" that influence biological phenotype in a fashion that is not dependent on the underlying primary DNA sequence. One setting in which epigenetics is likely to have a profound influence on biological phenotype is during intrauterine development. In this context there is a defined and critical window during which balanced homeostasis is essential for normal fetal growth and development. We have carried out a detailed structural and functional analysis of the placental epigenome at its maternal interface. Specifically, we performed genome wide analysis of DNA methylation in samples of chorionic villus (CVS) and maternal blood cells (MBC) using both commercially available and custom designed microarrays. We then compared these data with genome wide transcription data for the same tissues. In addition to the discovery that CVS genomes are significantly more hypomethylated than their MBC counterparts, we identified numerous tissue-specific differentially methylated regions (T-DMRs). We further discovered that these T-DMRs are clustered spatially along the genome and are enriched for genes with tissue-specific biological functions. We identified unique patterns of DNA methylation associated with distinct genomic structures such as gene bodies, promoters and CpG islands and identified both direct and inverse relationships between DNA methylation levels and gene expression levels in gene bodies and promoters respectively. Furthermore, we found that these relationships were significantly associated with CpG content. We conclude that the early gestational placental DNA methylome is highly organized and is significantly and globally associated with transcription. These data provide a unique insight into the structural and regulatory characteristics of the placental epigenome at its maternal interface and will drive future analyses of the role of placental dysfunction in gestational disease.

Show MeSH