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

Julien Bricambert (1) , Marie-Clotilde Alves-Guerra (1) , Pauline Esteves , Carina Prip-Buus (1) , Justine Bertrand-Michel (2) , Hervé Guillou , Christopher Chang , Mark Vander Wal , Francois Canonne-Hergaux (3) , Philippe Mathurin (4, 5) , Violeta Raverdy , François Pattou (6) , Jean Girard (7) , Catherine Postic (1) , Renaud Dentin (1)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 IRSD - Institut de Recherche en Santé Digestive
4 Hôpital Claude Huriez [Lille]
5 LIRIC - Lille Inflammation Research International Center - U 995
6 Service de chirurgie générale et endocrinienne
7 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins

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

Domaines: Sciences du Vivant [q-bio]

Julien Bricambert, Marie-Clotilde Alves-Guerra, Pauline Esteves, Carina Prip-Buus, Justine Bertrand-Michel, et al.. The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity. Nature Communications, 2018, 9 (1), ⟨10.1038/s41467-018-04361-y⟩. ⟨hal-02122655⟩