In-depth characterization of the placental imprintome reveals novel differentially methylated regions across birth weight categories

ABSTRACT

Imprinted genes play a pivotal role in placental processes underlying fetal development, and much interest centers on discerning whether these loci, via changes in DNA methylation and/or gene expression, inform disruptions in appropriate fetal growth. In this study, we comprehensively profiled DNA methylation across the placental imprintome and assessed the relationship with gene expression levels and aberrant fetal growth.

Placental DNA methylation across 153 imprinted loci, including imprint control regions (ICR) and surrounding non-ICR regions, was surveyed using the Nimblegen TruSeq bisulfite sequencing platform among participants enrolled in the Rhode Island Child Health Study (RICHS, n = 163). Methylation and gene expression associations were assessed using eQTM analysis. Differential methylation analysis contrasting small (SGA) and large for gestational age (LGA) infants against appropriate for gestational age (AGA) infants was assessed using the DMRcate R package.

We identified 34 SGA-related differentially methylated regions (DMRs) and 9 LGA-related DMRs (FDR<0.05), and these BW-DMRs predominated in promoter and intronic regions. We observed overall hypomethylation among SGA-DMRs overlapping maternally expressed (paternally imprinted) genes while no parent-of-origin effect was observed among LGA DMRs. Three BW-DMRs, mapping to GABRG3, IGF1R and MEST, were common to SGA and LGA placenta. We did not observe significant correlations between BW-DMR-associated CpG methylation and gene expression levels.

We report the first in-depth characterization of the placental imprintome in a population-wide setting. Our findings reveal growth-related differences in methylation without concomitant expression differences in regions that extend beyond typically interrogated imprinted loci, highlighting potentially novel placental biomarkers of growth and development.

KEYWORDS:

• Methylation
• imprinting
• placenta
• Birth Weight

Acknowledgments

This work is supported by NIH-NIMH R01MH094609, NIH-NIEHS R01ES022223, NIH-NIEHS R01ES022223-03S, NIH-NIEHS R24ES028507, NIH-NIEHS P30ES023515, and NIH-NIEHS K99ES029571-01. We would like to thank the Epigenomics Core at Weill Cornell, particularly Alicia Alonso and Thadeous J. Kacmarczyk, for the library preparation, sequencing and preprocessing of the generated data.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

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Additional information

Funding

This work was supported by the National Institute of Environmental Health Sciences [R01ES022223-03S];National Institute of Environmental Health Sciences [R01ES022223];National Institute of Environmental Health Sciences [K99ES029571-01];National Institute of Environmental Health Sciences [R24ES028507];National Institute of Environmental Health Sciences [P30ES023515];National Institute of Mental Health [R01MH094609].