Histone Deacetylase 1 (HDAC1) Negatively Regulates Thermogenic Program in Brown Adipocytes via Coordinated Regulation of Histone H3 Lysine 27 (H3K27) Deacetylation and Methylation

Abstract

Inhibiting class I histone deacetylases (HDACs) increases energy expenditure, reduces adiposity, and improves insulin sensitivity in obese mice. However, the precise mechanism is poorly understood. Here, we demonstrate that HDAC1 is a negative regulator of the brown adipocyte thermogenic program. The Hdac1 level is lower in mouse brown fat (BAT) than white fat, is suppressed in mouse BAT during cold exposure or ␤ 3 -adrenergic stimulation, and is down-regulated during brown adipocyte differentiation. Remarkably, overexpressing Hdac1 profoundly blocks, whereas deleting Hdac1 significantly enhances, ␤-adrenergic activation-induced BAT-specific gene expression in brown adipocytes. ␤-Adrenergic activation in brown adipocytes results in a dissociation of HDAC1 from promoters of BAT-specific genes, including uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor ␥ co-activator 1␣ (Pgc1␣), leading to increased acetylation of histone H3 lysine 27 (H3K27), an epigenetic mark of gene activation. This is followed by dissociation of the polycomb repressive complexes, including the H3K27 methyltransferase enhancer of zeste homologue (EZH2), suppressor of zeste 12 (SUZ12), and ring finger protein 2 (RNF2) from (and concomitant recruitment of H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) to) Ucp1 and Pgc1␣ promoters, leading to decreased H3K27 trimethylation, a histone transcriptional repression mark. Thus, HDAC1 negatively regulates the brown adipocyte thermogenic program, and inhibiting Hdac1 promotes BAT-specific gene expression through a coordinated control of increased acetylation and decreased methylation of H3K27, thereby switching the transcriptional repressive state to the active state at the promoters of Ucp1 and Pgc1␣. Targeting HDAC1 may be beneficial in prevention and treatment of obesity by enhancing BAT thermogenesis.

Transcriptional and epigenetic control of brown and beige adipose cell fate and function

“…Adipose-selective transgenic expression of FOXC2 increases intracellular cAMP levels by increasing the expression of PKA (the RIα subunit) and promotes beige adipocyte thermogenesis in WAT 62 . By contrast, histone deacetylase HDAC1 (and HDAC2) inhibits thermogenesis through deacetylation of H3K27 on the regulatory regions of Ucp1 , which then inhibits CREB and ATF2 mediated transcription 74 . Intriguingly it has been recently found that casein kinase 2 (CK2) activity in response to β-AR signalling is preferentially increased in WAT and inhibits the thermogenic programme in this tissue.…”

Brown and Beige Adipose Tissues in Health and Disease

“…LSD1 is recruited to brown/beige adipogenic enhancers through its interactions with transcription factors Nrf1 and Zfp516 (71, 267). Cold exposure decreases histone deacetylase 1 (Hdac1) levels in BAT, and β adrenergic signaling decreases the binding of Hdac1 to the UCP1 and PGC1α promoters in brown adipocytes, leading to an increase in active epigenetic H3K27ac mark (181). Concurrently, β adrenergic signaling stimulates dissociation of enhancer of zeste homologue (Ezh2) and suppressor of zeste 12 (SUZ12), leading to a decrease in repressive epigenetic mark H3K27me3 at the UCP1 and PGC1α promoters (181).…”

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

“…The favourable open chromatin structure for Ucp1 transcriptional activation after β-AR stimulation has been previously reported in cultured brown adipocyte, demonstrated by a significant increase of H3K27ac in both the Ucp1 and Pgc1α promoter regions [12]. However, which factors regulate behind this phenomenon is still unclear.…”