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

Julien Bricambert, Marie-Clotilde Alves-Guerra, Pauline Esteves, Carina Prip-Buus, Justine Bertrand-Michel, Hervé Guillou, Christopher J. Chang, Mark N. Wal, François Canonne-Hergaux, Philippe Mathurin, Violeta Raverdy, François Pattou, Jean Girard, Catherine Postic and Renaud Dentin ()
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Julien Bricambert: INSERM, U1016, Institut Cochin
Marie-Clotilde Alves-Guerra: INSERM, U1016, Institut Cochin
Pauline Esteves: INSERM, U1016, Institut Cochin
Carina Prip-Buus: INSERM, U1016, Institut Cochin
Justine Bertrand-Michel: INSERM, Plateforme MetaToul
Hervé Guillou: Toxicologie Intégrative et Métabolisme
Christopher J. Chang: University of California
Mark N. Wal: University of California
François Canonne-Hergaux: INSERM U1043-CPTP
Philippe Mathurin: Lille University Hospital
Violeta Raverdy: U859 Biotherapies for Diabetes
François Pattou: U859 Biotherapies for Diabetes
Jean Girard: INSERM, U1016, Institut Cochin
Catherine Postic: INSERM, U1016, Institut Cochin
Renaud Dentin: INSERM, U1016, Institut Cochin

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04361-y

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