A Locus Control Region Generates Distinct Active Placental Lactogen And Inactive Growth Hormone Gene Domains In Term Placenta That Are Disrupted With Obesity

Abstract

A Placental villi include an outer layer of syncytiotrophoblasts (STBs) and an inner layer of cytotrophoblasts (CTBs) that fuse to generate STBs in pregnancy. While activation of the single locus containing the human (h) placental lactogen (hPL) genes (hPL-A/CSH1 and hPL-B/CSH2) begins in the CTBs, their expression in STBs requires further epigenetic modifications as well as interactions between locus control region (LCR) and gene regulatory sequences. No transcription factor that limits or facilitates hPL LCR/gene interactions for locus activation is reported but the paternally-expressed gene 3 (PEG3/PW1) transcription factor is a candidate. PEG3 is expressed by villous CTBs but not STBs, and putative PEG3 sites were identified in the hPL LCR and promoter sequences. Furthermore, dysregulation of both hPL and PEG3 gene expression have been linked to peripartum depression. Using CTB-like JEG-3 cells, we show PEG3 binding to hypersensitive sites (HS III-V) within the LCR, and that hPL transcript levels increase with PEG-3 knockdown. In term placenta, PEG3 binding at placenta-specific HS IV was increased with maternal obesity, where a decrease in hPL RNA levels is seen, while PEG3 binding was reduced in women with obesity who develop insulin-treated gestational diabetes mellitus (O/GDM+Ins), where increased hPL gene expression is observed. Chromatin conformation capture revealed distinct hPL gene domain interactions that are modified with maternal obesity but largely reversed in O/GDM+Ins, correlating with PEG3 binding. Thus, decreased PEG3 binding may be required for hPL domain generation and expression during CTB to STB transition.