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

Nat Commun. 2018 May 29;9(1):2092. doi: 10.1038/s41467-018-04361-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cells, Cultured
  • Demethylation*
  • Enzyme Activation
  • Glucose / metabolism
  • Glutathione / biosynthesis
  • Histone Demethylases / metabolism*
  • Histones / metabolism*
  • Homeodomain Proteins / metabolism*
  • Humans
  • Liver / pathology
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Obesity / pathology*
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Pentose Phosphate Pathway / physiology
  • Promoter Regions, Genetic / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Histones
  • Homeodomain Proteins
  • Mlxipl protein, mouse
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Histone Demethylases
  • PHF2 protein, mouse
  • Glutathione
  • Glucose