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Title: Maternal regulation of SATB2 in osteo-progeniters impairs skeletal development in offspring

Author
item CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC)
item ZHAO, HAIJUN - Arkansas Children'S Nutrition Research Center (ACNC)
item LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/3/2019
Publication Date: 12/23/2019
Citation: Chen, J., Zhao, H., Lazarenko, O.P., Blackburn, M.L., Shankar, K. 2019. Maternal regulation of SATB2 in osteo-progeniters impairs skeletal development in offspring. Journal of Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.201901901R.
DOI: https://doi.org/10.1096/fj.201901901R

Interpretive Summary: Effects of high fat diet-induced gestational obesity on fetal bone development and offspring adult bone metabolism are not well understood. Here, we made a maternal obesity rat model by feeding a high fat diet pre- and during pregnancy for total 12 weeks. Maternal obesity resulted in significantly decreased fetal bone development. Using molecular biology techniques, it was discovered that a gene (SATB) important to bone-forming cells (osteoblasts) was repressed in offspring from obese mothers, and this appeared to be due to a negative regulator called Ezh2. To confirm this, an Ezh2 gene knockout mouse model was used to investigate the effects of maternal obesity on both fetal skeletal development and mechanisms linking maternal obesity to osteoblast differentiation in offspring. The results were consistent with the idea that decreased fetal bone development from obese mouse dams is due to Ezh2-mediated bone-specific gene SATB2 DNA modifications ("epigenetic" methylation). The Ezh2 gene knockout mouse model also showed increased bone density in the trabecular bone compartment, indicative of Ezh2 being a negative regulator of bone growth. Molecular signaling data also linked maternal obesity and decreased osteoblast bone cell development in human stem cells derived from umbilicus of babies born to overweight/obese mothers. Our findings revealed that maternal HFD-induced obesity in rodents may be associated with decreasing of fetal pre-osteoblastic cell differentiation, under epigenetic control of SATB2 expression via Ezh2-dependent mechanisms. Results using cell culture suggest that these same mechanisms of obesity-regulated bone growth can also occur in human cells.

Technical Abstract: Nutritional status during intrauterine and/or early postnatal life has substantial influence on adult offspring health. Along these lines, there is a growing body of evidence illustrating that high fat diet (HFD)-induced maternal obesity can regulate fetal bone development. Thus, we investigated the effects of maternal obesity on both fetal skeletal development and mechanisms linking maternal obesity to osteoblast differentiation in offspring. Embryonic osteogenic calvarial cells (EOCCs) were isolated from fetuses at gestational day 18.5 (E18.5) of HFD-induced obese rat dams. We observed impaired differentiation of EOCCs to mature osteoblasts from HFD obese dams. ChIP-seq-based genome-wide localization of the repressive histone mark H3K27me3 (mediated via the polycomb histone methyltransferase, Ezh2) showed that this phenotype was associated with increased enrichment of H3K27me3 on the gene of SATB2, a critical transcription factor required for osteoblast differentiation. Knockdown of Ezh2 in EOCCs and ST2 cells increased SATB2 expression; while Ezh2 overexpression in EOCCs and ST2 cells decreased SATB2 expression. These data were consistent with experimental results showing strong association between H3K27me3, Ezh2 and SATB2 in cells from rats and humans. Pre-osteoblast specific Ezh2 deletion (Ezh2-Osx CKO) confirmed increased SATB2 mRNA and protein expression in bones from Ezh2flox/flox Osx-Cre+ CKO mice compared with those from Ezh2flox/+Cre+, Cre+, Ezh2flox/flox Cre-, Ezh2flox/+Cre- and wild type mice, and increased trabecular bone mass compared with those from Cre+ control mice. These findings indicate that maternal HFD-induced obesity in mice may be associated with decreasing of fetal pre-osteoblastic cell differentiation, under epigenetic control of SATB2 expression via Ezh2-dependent mechanisms.