A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism

Abstract

Disruption of the circadian clock exacerbates metabolic diseases including obesity and diabetes. Here we show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.

Circadian regulation of lipid metabolism

“…For example, thousands of DNAbinding sites in mouse liver are rhythmically occupied by BMAL1, including genes involved in sterol and TAG metabolic pathways (49,50) . Similarly, the circadian cistromes for REV-ERBα, nuclear receptor corepressor and histone deacetylase 3 overlap extensively and are enriched for genes involved in lipid metabolism (51)(52)(53) . Circadian rhythms in genome-wide occupancy for BMAL1, REV-ERBα and REV-ERBβ show strong overlap for metabolic pathways and transcriptional regulators in the liver (52) , and similar findings have been reported for other core clock proteins (BMAL1, CLOCK, NPAS2, PER1, PER2, CRY1 and CRY2) (54) .…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Plusieurs histones désacétylases comme Sirt1 (sirtuine 1) et HDAC3, présentes dans le complexe Rev-erb/NcoR (nuclear receptor co-repressor protein), permettent ainsi l'inté-gration de ces signaux. La délétion de HDAC3 entraîne des désordres métaboliques, ainsi qu'un dérèglement de l'horloge [4]. D'autres modifications, telles que la méthylation et le remodelage de la chromatine, jouent un rôle à part entière dans le contrôle circadien du métabolisme (voir [5] pour revue).…”

Targeting chromatin remodelers to treat hepatocellular carcinoma

“…Nonetheless, liver-specific inhibition of SAHA-targeted class I HDAC3 gene causes steatosis and disruption of circadian rhythms in normal liver parenchyma by impinging on multiple signaling pathways in mice. 4 Without well-designed in vivo studies it will be hard to assess the efficacy of epigenetic combinatorial HCC therapy and the effects of these drugs on healthy surrounding liver tissue.…”

“…2 Subsequent studies demonstrate that ALC1 is specifically targeted to the sites of DNA damage through interaction with PARP1 and regulates chromatin remodeling during the process of DNA repair. 3,4 Consequently, knockdown of ALC1 results in increased cellular sensitivity to specific DNA damaging agents phleomycin and H 2 O 2 . 3 Given that the HepG2 cells expressing high levels of ALC1 2 are sensitive to both PARP and HDAC inhibitors, 1 there is increasing interest in seeing the expression status of ALC1 in SNU-398 and SNU-449 cell lines, with sensitive versus resistant phenotype to both enzymatic inhibitors, respectively.…”