The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
Julien BricambertMarie-Clotilde Alves-GuerraPauline EstevesCarina Prip-BuusJustine Bertrand-MichelHervé GuillouChristopher J ChangMark N Vander WalFrançois Canonne-HergauxPhilippe MathurinVioleta RaverdyFrancois PattouJean GirardCatherine PosticRenaud DentinPublished in: Nature communications (2018)
Aberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD.
Keyphrases
- transcription factor
- insulin resistance
- dna methylation
- oxidative stress
- genome wide
- genome wide identification
- high fat diet induced
- metabolic syndrome
- dna damage
- weight loss
- type diabetes
- gene expression
- adipose tissue
- dna binding
- high fat diet
- skeletal muscle
- binding protein
- weight gain
- polycystic ovary syndrome
- fatty acid
- cell cycle
- nuclear factor
- copy number
- diabetic rats
- ischemia reperfusion injury
- bioinformatics analysis
- induced apoptosis
- signaling pathway
- heat shock
- lps induced
- blood pressure
- cancer therapy
- toll like receptor
- physical activity