Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 315, Issue 4, Pages E435-E445Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00042.2018
Keywords
chorionic somatomammotropin; gene promoter; locus control region; maternal obesity; pituitary and placental growth hormone
Categories
Funding
- Canadian Institutes of Health Research
- Research Manitoba
- University of Manitoba
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The human (h) placental lactogenic hormone chorionic somatomammotropin (CS) is highly produced during pregnancy and acts as a metabolic adaptor in response to maternal insulin resistance. Maternal obesity can exacerbate this resistance, and a >75% decrease in CS RNA levels was observed in term placentas from obese vs. lean women. The genes coding for hCS (hCS-A and hCS-B) and placental growth hormone (hGH-V) as well as the hCS-L pseudogene and pituitary growth hormone (GH) gene (hGH-N) are located at a single locus on chromosome 17. Three remote hypersensitive sites (HS III-V) located > 28 kb upstream of hGH-N as well as local hCS gene promoter and enhancer regions are implicated in hCS gene expression. A placenta-specific chromosomal architecture, including interaction between HS III-V and hCS but not hGH gene promoters, was detected in placentas from lean women (BMI <25 kg/m(2)) by using the chromosome conformation capture assay. This architecture was disrupted by prepregnancy maternal obesity (BMI <35 kg/m(2)), resulting in a predominant interaction between HS III and the hGH-N promoter, which was also observed in nonplacental tissues. This was accompanied by a decrease in hCS levels, which was consistent with reduced RNA polymerase II and CCAAT/enhancer-binding protein-beta association with individual hCS promoter and enhancer sequences, respectively. Thus, pre-pregnancy maternal obesity disrupts the placental hGH/CS gene locus chromosomal architecture. However, based on data from obese women who develop GDM, insulin treatment partially recapitulates the chromosomal architecture seen in lean women and positively affects hCS production, presumably facilitating prolactin receptor-related signaling by hCS.
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