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

Nature Communications
Julien BricambertRenaud Dentin

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.

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Citations

Sep 7, 2019·Proceedings of the National Academy of Sciences of the United States of America·Stella PappaMarian A Martínez-Balbás
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May 29, 2021·Frontiers in Endocrinology·Hannah MaudeInês Cebola
May 29, 2021·Journal of Molecular Cell Biology·Bangliang HuangYi Zheng

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Datasets Mentioned

BETA
GSE61575
GSE61576

Methods Mentioned

BETA
co-immunoprecipitation
pull down
pull-down
ChIP-seq
carbonylation
ChIP
biopsies
ubiquitination
immunoprecipitation
ELISA

Clinical Trials Mentioned

NCT01129297

Software Mentioned

Bioconductor R
EASE35
MEME Suite
DAVID
QuanLynx
Illumina Genome Analysis pipeline
MEME
Partek GS
UCSC browser
GraphPad Prism

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