The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation

Zha, Lin; Li, Fenfen; Wu, Rui; Artinian, Liana; Rehder, Vincent; Yu, Liqing; Liang, Houjie; Xue, Bingzhong; Shi, Hang

doi:10.1074/jbc.m115.662650

Cited by 70 publications

(69 citation statements)

References 61 publications

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“…The expression of Brachyury was differentially induced in Utx -deficient adipocytes depending on the clones (Fig 3D). Recently, Utx has been reported to promote the expressions of genes responsible for thermogenesis in brown adipose tissue [24,25]. In our experiment, Utx deficiency did not affect the expression of Prdm16 , Pgc1 alpha , or Ucp1 , which are critical for thermogenesis in brown adipose tissue (Fig 3E).…”

Section: Resultssupporting

confidence: 53%

The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stage-dependent manner

et al. 2017

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Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes. Utx-deficient mESCs showed diminished potential to differentiate to adipocytes compared to that of controls. In contrast, Utx-deficient preadipocytes showed enhanced differentiation to adipocytes. Microarray analyses indicated that the β-catenin/c-Myc signaling pathway was differentially regulated in Utx-deficient cells during adipocyte differentiation. Therefore, our data suggest that Utx governs adipogenesis by regulating c-Myc in a differentiation stage-specific manner and that targeting the Utx signaling pathway could be beneficial for the treatment of obesity, diabetes, and congenital utx-deficiency disorders.

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Section: Resultssupporting

confidence: 53%

The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stage-dependent manner

et al. 2017

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“…In diabetic mice, we also detected subtle and variable shifts in dysglycemia with GSK-J4 treatment, including a marginal decrease in blood glucose but an increase in glycated hemoglobin levels. Although the metabolic effects of Jmjd3 and UTX are mostly unknown, UTX upregulation was recently shown to promote the browning of adipose tissue (43), and thus its inhibition could theoretically impair energy expenditure.…”

Section: Discussionmentioning

confidence: 99%

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Majumder¹,

Thieme²,

Batchu³

et al. 2017

Journal of Clinical Investigation

104

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“…Brown adipocyte differentiation is associated with increased expression of Jmjd3 (a H3K27me3 demethylase), ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, demethylating H3K27me2–3), and lysine-specific histone demethylase 1 (LSD1, demethylating both H3K4me1–3 and H3K9me1–3) (235, 267, 359). Jmjd3 and UTX demethylate H3K27me3, a repressive epigenetic mark, at the promoters of UCP1 and other brown adipocyte-selective genes, thereby upregulating these genes (235, 359). Cold exposure or β3 agonist stimulation increase LSD1 expression in iWAT (71).…”

Section: Genetic and Epigenetic Regulation Of Brown And Beige Fat Thementioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

137

113

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation

Cited by 70 publications

References 61 publications

The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stage-dependent manner

The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stage-dependent manner

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

Brown and Beige Adipose Tissues in Health and Disease

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