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.

Direct Transcriptional Repression of Zfp423 by Zfp521 Mediates a Bone Morphogenic Protein-Dependent Osteoblast versus Adipocyte Lineage Commitment Switch

“…Our findings therefore support the growing evidence that lineage determination of mesenchymal precursor cells is epigenetically regulated through histone modifications (35,36). DNA methylation in the Zfp423 promoter was also observed in adipose tissue from mice subjected to an obesogenic diet (34). Additional studies will be required to further elucidate the epigenetic mechanism by which Zfp521 alters Zfp423 expression.…”

“…The mechanisms by which Zfp423 expression is regulated are poorly understood. Recently, Zfp423 promoter activity in fetal tissues has been linked to maternal obesity (34), and in silico analysis of transcription factor motifs identified a classical enhancer region within Zfp423 intron 5 (31). Our ChIP analysis provides the first data demonstrating that Zfp521 regulates the expression of Zfp423 by associating with chromatin and promoting chromatin modifications, such as H3K9 acetylation and H3K9me3, at the Zfp423 promoter, pointing to a role for Zfp521 in epigenetic regulation of the transcription of a subset of genes involved in cell lineage determination.…”

Depot- and sex-specific effects of maternal obesity in offspring’s adipose tissue

“…However, maternal obesity before conception and gestation is also able to program similar outcomes during the embryonic period. Indeed, despite normal fetal weight, fetus from mice fed a HF diet prior and throughout pregnancy displayed larger adipocytes (Murabayashi et al 2013, Umekawa et al 2015 and increased mRNA expression levels of Zfp423, a key transcriptional factor initiating adipogenic commitment (Yang et al 2013). Adult mouse offspring also exhibited increased mRNAs levels of several genes involved in de novo lipogenesis and lipid droplet size in visceral WAT (Dahlhoff et al 2014).…”

“…Differences in fat cell embryonic origin, development, genetic, and hormonal sensitivity may result in a depot-specific programming effects that may predispose offspring to higher adiposity (Öst & Pospisilik 2015). Indeed, maternal obesity in mice induces increased gene expression of Zfp423 with lower promoter methylation levels in fetal offspring (Yang et al 2013). Similarly, weanling rats from obese dams display increased Zfp423 and C/Ebpβ mRNA expression levels with alterations in DNA methylation of CpG sites (Borengasser et al 2013).…”

ZNF423: Transcriptional modulation in development and cancer

“…19 Recently, 3 independent research groups have presented data on the epigenetic regulation of ZNF423 expression. 5,17,20 Epigenetic changes, such as DNA methylation and histone modifications, are key regulators of transcription. [21][22][23] Harder et al described a CpG island (CGI) situated between the alternative ZNF423a and ZNF423b promoters (Fig.…”