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. 2020 Sep:96:221-230.
doi: 10.1016/j.reprotox.2020.07.007. Epub 2020 Jul 25.

Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling

Alexis Payton  1 , Jeliyah Clark  1 , Lauren Eaves  1 , Hudson P Santos Jr  2 , Lisa Smeester  3 , Jacqueline T Bangma  1 , T Michael O'Shea  4 , Rebecca C Fry  5 , Julia E Rager  6
Affiliations

Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling

Alexis Payton et al. Reprod Toxicol. 2020 Sep.

Abstract

Birth weight (BW) represents an important clinical and toxicological measure, indicative of the overall health of the newborn as well as potential risk for later-in-life outcomes. BW can be influenced by endogenous and exogenous factors and is known to be heavily impacted in utero by the health and function of the placenta. An aspect that remains understudied is the influence of genomic and epigenomic programming within the placenta on infant BW. To address this gap, we set out to test the hypothesis that genes involved in critical placental cell signaling are associated with infant BW, and are likely regulated, in part, through epigenetic mechanisms based on microRNA (miRNA) mediation. This study leveraged a robust dataset based on 390 infants born at low gestational age (ranged 23-27 weeks) to evaluate genome-wide expression profiles of both mRNAs and miRNAs in placenta tissues and relate these to infant BW. A total of 254 mRNAs and 268 miRNAs were identified as associated with BW, the majority of which showed consistent associations across placentas derived from both males and females. BW-associated mRNAs were found to be enriched for important biological pathways, including glycoprotein VI (the major receptor for collagen), human growth, and hepatocyte growth factor signaling, a portion of which were predicted to be regulated by BW-associated miRNAs. These miRNA-regulated pathways highlight key mechanisms potentially linking endogenous/exogenous factors to changes in birth outcomes that may be deleterious to infant and later-in-life health.

Keywords: Birth outcome; Birth weight; Genomic signature; Mechanisms; Placenta; microRNAs.

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Conflict of interest statement

Conflict of Interest

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. MAplots of mean (A) mRNA and (B) miRNA expression levels vs. fold change in expression associated with infant BW across human placenta tissues.
Beta estimates represent the change in expression associated with one unit increase in BW and are plotted as log2 transformed values. mRNAs and miRNAs that were identified as significantly (FDR < 0.10) associated with BW are red, and those that were not significantly associated are displayed in grey. Only mRNAs and miRNAs expressed above background are displayed.
Figure 2.
Figure 2.
Overlap between (A) mRNAs and (B) miRNAs identified as associated with BW within the overall, collective analyses, in comparison to the sex-stratified analyses.
Figure 3.
Figure 3.. Example BW-associated mRNAs predicted to be regulated by miRNAs.
The four most significantly correlated expression level pairings are shown, specifically including (A) paternally expressed 10 (PEG10) and miR-6088; (B) transcriptional adaptor 1 (TADA1) and miR-4800–5p; (C) heterogeneous nuclear ribonucleoprotein C (HNRNPC) and miR-2392; and (D) COMM domain containing 2 (COMMD2) and miR-6088. These graphs were made with variance stabilized normalized counts.
Figure 4.
Figure 4.. Proteins encoded by BW-associated genes involved in GP6 signaling in the placenta.
Direct interactions are shown in solid lines and indirect in dashed lines.
Figure 5.
Figure 5.. Network showing biological interactions between proteins encoded by mRNAs associated with infant BW, a portion of which are predicted to be regulated by BW-associated miRNAs in human placenta tissues.
Molecules with BW-associated changes are colored, and molecules with associated signaling are white. Direct interactions are shown in solid lines and indirect in dashed lines.
See this image and copyright information in PMC

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