Human growth gene family chromosomal architecture is affected by maternal obesity, gestational diabetes and insulin treatment

Human placental chorionic somatomammotropin (CS) ‐A and B, and growth hormone variant (GH‐V) are placental members of the human (h) growth hormone (GH) gene family. These genes are located at a single locus on chromosome 17 in tandem with the pituitary hGH gene (GH‐N). CS and GH‐V stimulate pancreatic β‐cells in the response to ‘normal’ pregnancy induced insulin resistance. Maternal obesity exacerbates this ‘resistance’ and decreases CS/GH‐V gene expression, increasing the risk for gestational diabetes (GDM). Looping together of hGH‐N promoter and remote (14.5–32 kilobases) upstream hGH/CS locus control region (LCR) sequences is essential for efficient gene expression in vivo . Recently, hGH‐N chromatin looping and gene expression were shown to be negatively affected by excess caloric intake. Thus, we have compared the effect of maternal obesity (BMI >35 kg/m 2 ) without or with the further complication of GDM and insulin treatment on the chromatin structure and expression of the hCS/GH‐V gene locus in pregnancy. Human CS‐A RNA was decreased with maternal obesity but increased to levels detected in placentas from obese women with insulin treatment. Chromatin conformation capture (3C) assay was used to assess the long‐range interaction between the remote LCR sequences that include three nuclease hypersensitive sites (HS III–V) in human placental syncytiotrophoblasts, with and more proximal regulatory sequences linked to CS/GH‐V gene expression. Recruitment of RNA polymerase II at the promoter regions was also assessed as an indication of transcriptional status by chromatin immunoprecipitation assay. Physical interactions between remote LCR and local regulatory regions of the CS genes, suggesting looping of intervening sequences, were detected in lean woman, but were disrupted by maternal obesity. The same disrupted chromosomal conformation was not seen in obese diabetic pregnant women treated with insulin. However, although evidence of chromatin looping involving LCR and local regulatory sequences was apparent, the pattern was distinct when compared to lean placental samples. Maternal obesity was associated with significant decreases in RNA polymerase II occupancy at the promoter regions. Insulin treatment in obese women with a diabetic condition, however, significantly muted the decrease in RNA polymerase II occupancy at the CS/GH‐V promoter regions, presumably reflecting the looping of regulatory regions that was observed. Thus, insulin treatment of obese women with GDM results in overall CS/GH‐V RNA levels comparable to those seen in lean women. Recovery of the CS transcript levels, however, does not correlate with the preservation of the three dimensional chromosomal structure of the placental GH gene locus as defined in normal pregnancies. These data suggest a vulnerability of the hGH/CS gene locus chromatin structure and genes to excess caloric intake in pregnancy but also some plasticity in terms of response. Support or Funding Information Funded by the Canadian Institutes of Health Research

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