The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity

Abstract

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.

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

“…Our results showed that 97% of PHF2 peaks localized on gene promoters, around the transcription start site (TSS) ( Fig. 1A), as it has been reported in a different cellular context (25).…”

“…S1B). The high overlapping suggests a required H3K4me2/3 mark for effective PHF2 binding at promoters as it is described (13,25). To better understand how PHF2 is targeted to the chromatin, we performed bioinformatics analysis that revealed the most statistically significant predicted PHF2 binding sites using the Homer de novo motif research tool.…”

“…Previous studies demonstrated that PHF2 demethylates mainly H3K9me2 (13,25). We thus analyzed the distribution of H3K9me2 in NSCs by performing ChIP-seq experiments and compared it with PHF2 genomic-associated regions.…”

Commentary: The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity

“…Importantly, the article by Bricambert et al ( 2018 ) fits well into the deepening of the role of Phf2 in metabolic diseases. Specifically, in a mouse model of HF/HSD-induced NAFLD, the authors demonstrated that even by the triggering of diet-induced hepatic steatosis, Phf2 concomitantly reduced lipotoxicity by increasing the production of mono-unsaturated fatty acids (MUFA), thus enhancing the MUFA/saturated fatty acids (SFA) ratio.…”

“…In this regard, a recent article published in Nature Communication (Bricambert et al, 2018 ) demonstrated that the histone demethylase Plant homeodomain finger 2 (Phf2) protects liver from NAFLD progression. The authors found that an over-expression/induction of Phf2 protected the liver from lipotoxicity and oxidative stress in models of a high-fat/high-sucrose diet (HF/HSD) dependent NAFLD.…”