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Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.

ABSTRACT: Class I histone deacetylase inhibitors (HDACis) enhance whole body energy expenditure and attenuate high fat diet-induced insulin resistance. However, it is not clear whether this is exerted directly through activating brown fat thermogenesis. Here, we find that pan-HDACi TSA exerts paradoxical effects on brown fat gene expression, as it inhibits the expression of Ucp1, Ppar? and Prdm16 in brown adipocytes, while promoting the expression of other brown fat-specific genes such as Pgc1?, Pgc1?, Acox1 and Cidea. Further studies indicate that class I HDACi MS-275 significantly increases; whereas class II HDACi MC-1568 markedly reduces, the expression of Ucp1 and other brown fat-specific genes in treated brown adipocytes. ChIP assay reveals an enhanced H3 acetylation at the Pgc1? promoter in MS-275-treated brown adipocytes; whereas the effect of MC-1568 is associated with up-regulation of retinoblastoma protein (Rb) and an enhanced acetylation of H3K27 at the Rb promoter. Loss of function studies indicate that Pgc1? up-regulation largely mediates the stimulatory effect of class I HDACis on the thermogenic program, whereas up-regulation of Rb may be responsible for the inhibitory effect of class II HDACis. Thus, our data suggest that class I and II HDACis have differential effects on brown fat thermogenic gene expression.

SUBMITTER: Rajan A

PROVIDER: S-EPMC6117331 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.

Rajan Anubama A Shi Hang H Xue Bingzhong B

Scientific reports 20180830 1

Class I histone deacetylase inhibitors (HDACis) enhance whole body energy expenditure and attenuate high fat diet-induced insulin resistance. However, it is not clear whether this is exerted directly through activating brown fat thermogenesis. Here, we find that pan-HDACi TSA exerts paradoxical effects on brown fat gene expression, as it inhibits the expression of Ucp1, Pparγ and Prdm16 in brown adipocytes, while promoting the expression of other brown fat-specific genes such as Pgc1α, Pgc1β, Ac ...[more]

PMID: 30166563

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Project description:Osteoblast differentiation requires the coordinated stepwise expression of multiple genes. Histone deacetylase inhibitors (HDIs) accelerate the osteoblast differentiation process by blocking the activity of histone deacetylases (HDACs), which alter gene expression by modifying chromatin structure. We previously demonstrated that HDIs and HDAC3 shRNAs accelerate matrix mineralization and the expression of osteoblast maturation genes (e.g. alkaline phosphatase, osteocalcin). Identifying other genes that are differentially regulated by HDIs might identify new pathways that contribute to osteoblast differentiation.To identify other osteoblast genes that are altered early by HDIs, we incubated MC3T3-E1 preosteoblasts with HDIs (trichostatin A, MS-275, or valproic acid) for 18 hours in osteogenic conditions. The promotion of osteoblast differentiation by HDIs in this experiment was confirmed by osteogenic assays. Gene expression profiles relative to vehicle-treated cells were assessed by microarray analysis with Affymetrix GeneChip 430 2.0 arrays. The regulation of several genes by HDIs in MC3T3-E1 cells and primary osteoblasts was verified by quantitative real-time PCR. Nine genes were differentially regulated by at least two-fold after exposure to each of the three HDIs and six were verified by PCR in osteoblasts. Four of the verified genes (solute carrier family 9 isoform 3 regulator 1 (Slc9a3r1), sorbitol dehydrogenase 1, a kinase anchor protein, and glutathione S-transferase alpha 4) were induced. Two genes (proteasome subunit, beta type 10 and adaptor-related protein complex AP-4 sigma 1) were suppressed. We also identified eight growth factors and growth factor receptor genes that are significantly altered by each of the HDIs, including Frizzled related proteins 1 and 4, which modulate the Wnt signaling pathway.This study identifies osteoblast genes that are regulated early by HDIs and indicates pathways that might promote osteoblast maturation following HDI exposure. One gene whose upregulation following HDI treatment is consistent with this notion is Slc9a3r1. Also known as NHERF1, Slc9a3r1 is required for optimal bone density. Similarly, the regulation of Wnt receptor genes indicates that this crucial pathway in osteoblast development is also affected by HDIs. These data support the hypothesis that HDIs regulate the expression of genes that promote osteoblast differentiation and maturation.

Dataset Information

Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.

Publications

Class I and II Histone Deacetylase Inhibitors Differentially Regulate Thermogenic Gene Expression in Brown Adipocytes.

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