Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome

Baptissart, Marine; Bradish, C.M.; Jones, Brie S; Walsh, Evan; Tehrani, Jesse; Marrero-Colon, Vicmarie; Mehta, Sanya; Jima, Dereje D.; Oh, Seh Hoon; Diehl, Anna Mae; Fougeray, Tiffany; Guillou, Hervé; Cowley, Michael

doi:10.1002/hep.32363

Cited by 9 publications

(2 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, the imprinted Gene Network (IGN) and the regulator Zac1 (Plag11) mediate the developmental cadmium‐induced NAFLD through direct binding of Zac1 to the Pparγ promoter, thus inducing lipid accumulation (Riegl et al., 2023). Also, the overexpressed Zac1 binds the TGF‐β1 and COL6A2 promoters, linking maternal MetS exposure to the programming of juvenile NAFLD (Baptissart et al., 2022). As well, H19 promotes hepatic steatosis and obstructive cholestatic liver fibrosis (Liu et al., 2018; Song et al., 2017) and Grb10 regulates hepatic lipid metabolism in a cell‐autonomous manner (Luo et al., 2018; Madon‐Simon et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice

Shi,

Fan,

Yang

et al. 2024

Food Frontiers

View full text Add to dashboard Cite

Exposure to nutritional or environmental factors in early life determines susceptibility to nonalcoholic fatty liver disease (NAFLD). The effect of paternal preconceptional n‐3 polyunsaturated fatty acids (n‐3 PUFAs) on offspring NAFLD development remains unknown. Herein, a mouse model that weaning male mice (F0) received diet supplementation of normal n‐3 PUFA content (n‐6:n‐3 PUFA ratio = 4.3:1) or high n‐3 PUFA content (n‐6:n‐3 ratio = 1.5:1) for 12 weeks, and an n‐3 PUFA‐deficient diet as control, was used for the production of next generation. The F1 and F2 offspring were generated by mating F0 and F1 male mice with virgin female mice, respectively, and after weaning, were fed a high‐fat diet to induce NAFLD. The paternal n‐3 PUFA supplementation improved the scores of steatosis, inflammation and ballooning, and the fibrosis in the liver of two generations, with expressional upregulation of genes associated with fat oxidation (Atgl, Ppara, or Cpt1a), and downregulation of inflammatory genes (Ccl2, Tnf‐α, F4/80, CD206, or CD11c) and fibrosis genes (Tgf‐β, Timp1, or Col1a1). The lessened brown adipose tissue whitening, altered gut bacterial compositions, and altered expression of the imprinted genes (H19, Igf2, and Plagl1) might mediate the impact of paternal n‐3 PUFAs on offspring's NAFLD development, which was dose‐dependent. The data indicate that preconceptional higher paternal intake of n‐3 PUFAs might have intergenerational and transgenerational alleviating impact on obesity‐associated NAFLD development in the offspring through multiple pathways.

show abstract

Section: Discussionmentioning

confidence: 99%

Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice

Shi,

Fan,

Yang

et al. 2024

Food Frontiers

View full text Add to dashboard Cite

show abstract

“…For gene set enrichment analysis, the common DEGs between the 0 vs. 5 µM CdCl 2 exposed Jeg-3 cells and pcopGFP vs. pcopGFP-mTuna transfected cells detected through RNA-seq were analyzed via hypergeometric calculation as described previously ( Baptissart et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

LncRNA Tuna is activated in cadmium-induced placental insufficiency and drives the NRF2-mediated oxidative stress response

Simmers

Jima

Tsuji

et al. 2023

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Cadmium (Cd) is a toxic heavy metal found throughout the environment and one of the top ten toxicants of major public health concern identified by the World Health Organization. In utero Cd exposure causes fetal growth restriction, malformation, and spontaneous abortion; however, the mechanisms by which Cd impacts these outcomes are poorly understood. Cd accumulates in the placenta, suggesting that these negative outcomes may be a consequence of disrupted placental function and placental insufficiency. To understand the impact of Cd on gene expression within the placenta, we developed a mouse model of Cd-induced fetal growth restriction through maternal consumption of CdCl2 and performed RNA-seq on control and CdCl2 exposed placentae. The top differentially expressed transcript was the Tcl1 Upstream Neuron-Associated (Tuna) long non-coding RNA, which was upregulated over 25-fold in CdCl2 exposed placentae. Tuna has been shown to be critical for neural stem cell differentiation. However, within the placenta, there is no evidence that Tuna is normally expressed or functional at any developmental stage. To determine the spatial expression of Cd-activated Tuna within the placenta, we used in situ hybridization as well as placental layer-specific RNA isolation and analysis. Both methods confirmed the absence of Tuna expression in control samples and determined that Cd-induced Tuna expression is specific to the junctional zone. Since many lncRNAs regulate gene expression, we hypothesized that Tuna forms part of the mechanism of Cd-induced transcriptomic changes. To test this, we over-expressed Tuna in cultured choriocarcinoma cells and compared gene expression profiles to those of control and CdCl2 exposed cells. We demonstrate significant overlap between genes activated by Tuna overexpression and genes activated by CdCl2 exposure, with enrichment in the NRF2-mediated oxidative stress response. Herein we analyze the NRF2 pathway and show that Tuna increases NRF2/NRF2 both at the transcript and protein levels. Tuna drives increased NRF2 target gene expression, a result that is abrogated with the use of an NRF2 inhibitor, confirming that Tuna activates oxidative stress response genes through this pathway. This work identifies the lncRNA Tuna as a potential novel player in Cd-induced placental insufficiency.

show abstract

Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome

et al. 2022

Self Cite

View full text Add to dashboard Cite

Background and Aims Within the next decade, NAFLD is predicted to become the most prevalent cause of childhood liver failure in developed countries. Predisposition to juvenile NAFLD can be programmed during early life in response to maternal metabolic syndrome (MetS), but the underlying mechanisms are poorly understood. We hypothesized that imprinted genes, defined by expression from a single parental allele, play a key role in maternal MetS‐induced NAFLD, due to their susceptibility to environmental stressors and their functions in liver homeostasis. We aimed to test this hypothesis and determine the critical periods of susceptibility to maternal MetS. Approach and Results We established a mouse model to compare the effects of MetS during prenatal and postnatal development on NAFLD. Postnatal but not prenatal MetS exposure is associated with histological, biochemical, and molecular signatures of hepatic steatosis and fibrosis in juvenile mice. Using RNA sequencing, we show that the Imprinted Gene Network (IGN), including its regulator Zac1, is up‐regulated and overrepresented among differentially expressed genes, consistent with a role in maternal MetS‐induced NAFLD. In support of this, activation of the IGN in cultured hepatoma cells by overexpressing Zac1 is sufficient to induce signatures of profibrogenic transformation. Using chromatin immunoprecipitation, we demonstrate that Zac1 binds the TGF‐β1 and COL6A2 promoters, forming a direct pathway between imprinted genes and well‐characterized pathophysiological mechanisms of NAFLD. Finally, we show that hepatocyte‐specific overexpression of Zac1 is sufficient to drive fibrosis in vivo. Conclusions Our findings identify a pathway linking maternal MetS exposure during postnatal development to the programming of juvenile NAFLD, and provide support for the hypothesis that imprinted genes play a central role in metabolic disease programming.

show abstract

Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome

Cited by 9 publications

References 41 publications

Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice

Paternal preconceptional supplementation of n‐3 polyunsaturated fatty acids alleviates offspring nonalcoholic fatty liver disease in high‐fat diet‐induced obese mice

LncRNA Tuna is activated in cadmium-induced placental insufficiency and drives the NRF2-mediated oxidative stress response

Zac1 and the Imprinted Gene Network program juvenile NAFLD in response to maternal metabolic syndrome

Contact Info

Product

Resources

About