Genome-scale fluctuations in the cytotrophoblast epigenome over gestation and in placental pathologies
Dr. Yvonne Kim (UCSF)
Embryonic and extraembryonic development quickly diverges. Other than a globally hypomethylated genome, little is known about the epigenetic changes of placental cells throughout gestation. We profiled DNA methylation and activating/repressing histone modifications of cytotrophoblasts and four extraembryonic compartments in 2nd trimester and at term. Unexpectedly, in cytotrophoblasts, H3K9me3 occupancy precisely overlapped domains with even deeper DNA hypomethylation and repressed transcription. At term, immunoblotting and -localization revealed extensive depletion of this and other histone modifications that paralleled increased genome-wide DNA methylation, which included hundreds of promoters. Candidate enhancers within embryonic stem cell differentially methylated regions (DMRs) revealed pluripotency factors, while those within cytotrophoblast DMRs revealed transcription factor binding motifs and genes that regulate placental development. DNA methylation, RNA, and miRNA profiling of the extraembryonic compartments identified regional specializations and gestational age regulation. Cytotrophoblast mRNAs that were down-regulated at term were enriched for genes up-regulated in severe preeclampsia. Corresponding immunoanalyses of cytotrophoblast histone modifications showed strong H3K27ac upregulation in severe preeclampsia. ChIP-seq revealed retention at sites that normally carried this mark in 2nd trimester with subsequent loss at term. Thus, as gestation proceeded, certain cytotrophoblast histone modifications declined precipitously while, in a pregnancy complication, normal patterns were markedly perturbed. These data suggested an unusual genome-scale pattern of alterations in the abundance of epigenetic modifications over the lifetime of the placenta. Alterations in the histone pattern were associated with pregnancy complications, indicating a possible causative role.