title: Maternal gestational betaine supplementation-mediated suppression of hepatic cyclin D2 and presenilin1 gene in newborn piglets is associated with epigenetic regulation of the STAT3-dependent pathway.
abstract: Betaine, which donates methyl groups through methionine metabolism for DNA and protein methylation, is critical for epigenetic gene regulation, especially during fetal development. Here we fed gestational sows with control or betaine supplemented diets (3 g/kg) throughout the pregnancy to explore the effects of maternal betaine on hepatic cell proliferation in neonatal piglets. Neonatal piglets born to betaine-supplemented sows demonstrated a reduction of cell number and DNA content in the liver, which was associated with significantly down-regulated hepatic expression of cell cycle regulatory genes, cyclin D2 (CCND2) and presenilin1 (PSEN1). Moreover, STAT3 binding to the promoter of CCND2 and PSEN1 was also lower in betaine-exposed piglets, accompanied by strong reduction of STAT3 mRNA and protein expression, along with its phosphorylation at Tyr705 and Ser727 residues. Also, prenatal betaine exposure significantly attenuated upstream kinases of STAT3 signaling pathway (phospho-ERK1/2, phospho-SRC and phospho-JAK2) in the livers of neonates. Furthermore, the repressed STAT3 expression in the liver of betaine-exposed piglets was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3 on its promoter, together with significantly up-regulated expression of H3K27me3 and enhancer of zeste homolog 2 (EZH2) proteins, as well as miR-124a, which targets STAT3. Taken together, our results suggest that maternal dietary betaine supplementation during gestation inhibits hepatic cell proliferation in neonatal piglets, at least partly, through epigenetic regulation of hepatic CCND2 and PSEN1 genes via a STAT3-dependent pathway. These neonatal changes in cell cycle and proliferation regulation may lead to lower liver weight and hepatic DNA content at weaning.
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Demin
authors.initials: D
authors.lastname: Cai
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Medical cell biology, University of Uppsala, Uppsala SE-75123, Sweden.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, P. R. China. Electronic address: zhao.ruqian@gmail.com.
authors.forename: Ruqian
authors.initials: R
authors.lastname: Zhao
mesh_terms: D000821:Animal Feed; D000818:Animals; D000831:Animals, Newborn; D001622:Betaine / Q000737:chemistry*; D001835:Body Weight; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000378:metabolism*; D019175:DNA Methylation; D019587:Dietary Supplements; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D039382:Maternal Nutritional Physiological Phenomena; D035683:MicroRNAs / Q000378:metabolism; D009929:Organ Size; D011247:Pregnancy; D011270:Pregnancy, Animal; D053764:Presenilin-1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D015854:Up-Regulation
chemical_list: D056742:Cyclin D2; D035683:MicroRNAs; D053764:Presenilin-1; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D001622:Betaine
keywords: Cyclin D2; Epigenetic regulation; Maternal betaine diet; Presenilin1; STAT3