Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

Abstract

Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour 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 display 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 co-repressor (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.

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

“…While deletion of Hdac3 in Tregs led to increased expression of genes that were unaffected when HDAC3 was deleted in other cell types ( Figure 9F), for the most part there were similar changes in gene expression ( Figure 9G), as was reported for Hdac3 deletion in nonlymphoid cells (33)(34)(35)(36)(37)(38)(39)41). Overall, Hdac3 deletion led to altered expression of a wide variety of genes in Tregs, including those promoting activation of NF-κB and other proinflammatory pathways.…”

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

“…Similarly, the complex SIN3B-HDAC1/2 interacts with the circadian repressor CRY1 (28). In mice, the hepatic NCoR-HDAC3 complex is rhythmically recruited to chromatin via REV-ERBα, an event that regulates lipid metabolism in the liver by controlling the circadian epigenome at specific gene promoters (29,30). Thus, although more information is needed, it would seem that a variety of circadian repressive complexes exist and that their different functions could be specific for given autoregulatory loops.…”

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

“…The NCoR and HDAC3 cistromes are highly correlated with that of Rev-erba Sun et al 2011) and exhibit a circadian rhythm even though NCoR and HDAC3 levels do not oscillate throughout the day . The Rev-erba, NCoR, and HDAC3 cistromes are enriched for genes involved in lipid metabolism.…”