PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program

Harms, Matthew; Lim, Hee‐Woong; Ho, Yugong; Shapira, Suzanne N.; Ishibashi, Jeff; Rajakumari, Sona; Steger, David J.; Lazar, Mitchell A.; Won, Kyoung Jae; Seale, Patrick

doi:10.1101/gad.252734.114

Cited by 124 publications

(127 citation statements)

References 37 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…We found that EBF2 binds to ∼28,000 sites in the genome (Supplemental Excel File 1), many of which are in regions near brown fat-specific genes that show characteristic enhancer marks in BAT but not white adipose tissue (WAT) ( Fig. 1A; Harms et al 2015). A de novo motif search within EBF2-binding sites identified EBF as the top enriched motif, which validates the specificity of our ChIP-seq results (Supplemental Fig.…”

Section: Ebf2 Regulates Chromatin Accessibility At Brown Fat-specificsupporting

confidence: 78%

“…S1F). We performed genome-wide analysis anchoring on previously defined adipose depot-selective genes and regulatory regions (Supplemental Excel File 2; Harms et al 2015). On a genome-wide scale, loss of Ebf2 reduced RNA Pol II gene body occupancy and H3K27ac levels at brown fat-selective regulatory regions and increased Pol II and H3K27ac levels at white fat genes and regulatory regions (Fig.…”

Section: Ebf2 Regulates Chromatin Accessibility At Brown Fat-specificmentioning

confidence: 99%

See 1 more Smart Citation

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

et al. 2017

Self Cite

View full text Add to dashboard Cite

The transcription factor early B-cell factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes were unknown. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by deep sequencing) analyses in brown adipose tissue showed that EBF2 binds and regulates the activity of lineage-specific enhancers. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. We identified the histone reader protein DPF3 as a brown fat-selective component of the BAF complex that was required for brown fat gene programming and mitochondrial function. Loss of DPF3 in brown adipocytes reduced chromatin accessibility at EBF2-bound enhancers and led to a decrease in basal and catecholamine-stimulated expression of brown fat-selective genes. Notably, Dpf3 is a direct transcriptional target of EBF2 in brown adipocytes, thereby establishing a regulatory module through which EBF2 activates and also recruits DPF3-anchored BAF complexes to chromatin. Together, these results reveal a novel mechanism by which EBF2 cooperates with a tissue-specific chromatin remodeling complex to activate brown fat identity genes.

show abstract

Section: Ebf2 Regulates Chromatin Accessibility At Brown Fat-specificsupporting

confidence: 78%

Section: Ebf2 Regulates Chromatin Accessibility At Brown Fat-specificmentioning

confidence: 99%

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…These observations suggest that there is a mechanism that is preventing LSD1 from demethylating and inducing repression of those BAT-selective genes even if LSD1 is brought into close proximity together with PRDM16. Two reports showed that PRDM16 activates transcription of BAT-selective genes by recruiting MED1, a component of the mediator complex, to enhancer regions nearby (Harms et al 2015;Iida et al 2015). It is possible that the corecruitment of MED1 or additional members of the mediator complex by PRDM16 alters the enzymatic activity or substrate accessibility of LSD1 to render it nonoperative at loci near BAT-selective genes.…”

Section: Discussionmentioning

confidence: 99%

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

et al. 2016

View full text Add to dashboard Cite

Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.

show abstract

“…PPAR␥ ChIP-seq in 3T3-L1 is from GEO accession number GSE27450 (40), PPAR␥ ChIP-seq in EWAT is from GEO accession number GSE64458 (41), and PPAR␣ ChIP-seq in liver is from accession number GSE61817 (42). Histone 3 lysine 27 acetylation ChIP-seq in EWAT is from GEO accession number GSE63964 (43).…”

Section: Methodsmentioning

confidence: 99%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

show abstract

PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program

Cited by 124 publications

References 37 publications

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Contact Info

Product

Resources

About