title: Maternal obesity induces epigenetic modifications to facilitate Zfp423 expression and enhance adipogenic differentiation in fetal mice.
abstract: Maternal obesity (MO) predisposes offspring to obesity and type 2 diabetes despite poorly defined mechanisms. Zfp423 is the key transcription factor committing cells to the adipogenic lineage, with exceptionally dense CpG sites in its promoter. We hypothesized that MO enhances adipogenic differentiation during fetal development through inducing epigenetic changes in the Zfp423 promoter and elevating its expression. Female mice were subjected to a control (Con) or obesogenic (OB) diet for 2 months, mated, and maintained on their diets during pregnancy. Fetal tissue was harvested at embryonic day 14.5 (E14.5), when the early adipogenic commitment is initiated. The Zfp423 expression was 3.6-fold higher and DNA methylation in the Zfp423 promoter was lower in OB compared with Con. Correspondingly, repressive histone methylation (H3K27me3) was lower in the Zfp423 promoter of OB fetal tissue, accompanied by reduced binding of enhancer of zeste 2 (EZH2). Gain- and loss-of-function analysis showed that Zfp423 regulates early adipogenic differentiation in fetal progenitor cells. In summary, MO enhanced Zfp423 expression and adipogenic differentiation during fetal development, at least partially through reducing DNA methylation in the Zfp423 promoter, which is expected to durably elevate adipogenic differentiation of progenitor cells in adult tissue, programming adiposity and metabolic dysfunction later in life.
authors.affiliation: Department of Animal Sciences, Washington State University, Pullman, Washington.
authors.forename: Qi-Yuan
authors.initials: QY
authors.lastname: Yang
authors.forename: Jun-Fang
authors.initials: JF
authors.lastname: Liang
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Rogers
authors.forename: Jun-Xing
authors.initials: JX
authors.lastname: Zhao
authors.forename: Mei-Jun
authors.initials: MJ
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Du
mesh_terms: D017667:Adipocytes / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D009765:Obesity / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C484557:Ebfaz protein, mouse; D006657:Histones; D014157:Transcription Factors