Fetal Membrane Epigenetics

Abstract

The characteristics of fetal membrane cells and their phenotypic adaptations to support pregnancy or promote parturition are defined by global patterns of gene expression controlled by chromatin structure. Heritable epigenetic chromatin modifications that include DNA methylation and covalent histone modifications establish chromatin regions permissive or exclusive of regulatory interactions defining the cell-specific scope and potential of gene activity. Non-coding RNAs acting at the transcriptional and post-transcriptional levels complement the system by robustly stabilizing gene expression patterns and contributing to ordered phenotype transitions. Here we review currently available information about epigenetic gene regulation in the amnion and the chorion laeve. In addition, we provide an overview of epigenetic phenomena in the decidua, which is the maternal tissue fused to the chorion membrane forming the anatomical and functional unit called choriodecidua. The relationship of gene expression with DNA (CpG) methylation, histone acetylation and methylation, micro RNAs, long non-coding RNAs and chromatin accessibility is discussed in the context of normal pregnancy, parturition and pregnancy complications. Data generated using clinical samples and cell culture models strongly suggests that epigenetic events are associated with the phenotypic transitions of fetal membrane cells during the establishment, maintenance and termination of pregnancy potentially driving and consolidating the changes as pregnancy progresses. Disease conditions and environmental factors may produce epigenetic footprints that indicate exposures and mediate adverse pregnancy outcomes. Although knowledge is expanding rapidly, fetal membrane epigenetics is still in an early stage of development necessitating further research to realize its remarkable basic and translational potential.

Keywords: amnion; chorion; chromatin modifications; decidua; human pregnancy; non-coding RNAs; parturition.

FIGURE 1

Overall dynamics of epigenetic events in the amnion (A) and the decidua (B) during pregnancy. The blue, orange, and green block arrows indicate DNA methylation, histone modifications and miRNAs, respectively. Shading denotes changing levels and shifting genome-wide distributions. In the amnion, DNA methylation and histone modification patterns are established in early gestation to support pregnancy. Histone modification patterns change at term when labor-associated inflammatory genes are activated, and tissue remodeling occurs. Micro-RNAs stabilize the protective transcriptome until term, when levels decline concomitantly with inflammatory gene activation. In the decidua, hormonal influences (progesterone, estrogens, and cAMP signaling) trigger differentiation to the pregnancy-protective phenotype. The process involves major changes in histone modifications and miRNA expression but relatively modest alterations in DNA methylation. At term, histone modifications change, and key miRNAs decline to foster a proinflammatory and labor-promoting phenotype. Environmental adversities and disease conditions may be present throughout pregnancy but most likely impact on epigenetic events during periods of dynamic change. The resulting epigenetic “footprints” may influence gene expression patterns contributing to fetal membrane disfunction and may signify fetal exposure to unfavorable intrauterine conditions.