Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

Sep 9, 2011Cold Spring Harbor symposia on quantitative biology

Daily changes in gene regulation and liver fat production linked to HDAC3

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Abstract

Liver-specific knockout of HDAC3 in adult mice results in severe hepatic steatosis with enhanced de novo lipogenesis.

Increased expression of lipogenic genes is observed in mice lacking HDAC3 in the liver.
A genome-wide analysis shows circadian patterns of HDAC3 occupancy on lipid metabolism genes.
HDAC3 occupancy is inversely related to histone acetylation and RNA polymerase II recruitment.
The binding sites of HDAC3 and its partner NCoR significantly overlap with Rev-erbα, a key regulator of circadian rhythms.
Knockout of Rev-erbα also leads to hepatic steatosis and increased de novo lipogenesis.

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Circadian rhythms have evolved to anticipate metabolic needs across the 24-h light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse displays severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor corepressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.

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Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

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