Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

Loft, Anne; Forss, Isabel; Siersbæk, Majken; Schmidt, Søren Fisker; Larsen, Ann Sofie Bøgh; Madsen, Jesper Grud Skat; Pisani, Didier F.; Nielsen, Ronni; Aagaard, Mads M.; Mathison, Angela; Neville, Matt J.; Urrutia, Raúl; Karpe, Fredrik; Amri, Ez-Zoubir; Mandrup, Susanne

doi:10.1101/gad.250829.114

Cited by 134 publications

(143 citation statements)

References 85 publications

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“…Human subcutaneous adipocytes and 3T3-L1 cells show vastly different transcriptional programs (29) that indicate divergence between the two in vitro systems. In addition, rosiglitazone stimulates robust induction of UCP1 (45,46) and acquisition of the beige phenotype in primary human subcutaneous adipocyte models, but not in 3T3-L1 cells. Therefore, a previous report indicating Ubc9 knockdown disrupts adipogenesis in 3T3-L1 cells (47) does not extrapolate to the human subcutaneous adipocytes used in our experiments.…”

Section: Discussionmentioning

confidence: 97%

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Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Hartig

Bader

Abadie

et al. 2015

Molecular Endocrinology

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Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.

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Section: Discussionmentioning

confidence: 97%

“…Many factors that enable white adipocytes to express BAT genes have been identified including TZD-induced factors such as PGC1␣, PRDM16, and KLF11 (44,45).…”

Section: Discussionmentioning

confidence: 99%

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Hartig

Bader

Abadie

et al. 2015

Molecular Endocrinology

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“…However, TNF-induced gene repression in this context has received little attention. Based on the central role of super-enhancers in gene repression by TNF in SGBS adipocytes, combined with results showing that super-enhancers are highly cell-type specific Whyte et al 2013;Loft et al 2015), we hypothesized that TNF treatment should lead to acute repression of highly distinct gene programs in different cell types. To further investigate this, we analyzed publically available total RNA-seq and RNAPII ChIP-seq data from four additional human cell types (A549, IMR90, HeLa, and HUVEC) treated with vehicle or TNF for 1 h (Rao et al 2011;Jin et al 2013;Yang et al 2013;Brown et al 2014).…”

Section: Gene Repression By Tnf Is Highly Cell-type Specificmentioning

confidence: 99%

Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers

et al. 2015

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The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) is directly involved and required for the acute activation of the inflammatory gene program. Here, we show that the major transactivating subunit of NFκB, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high-occupancy sites within super-enhancers. Based on these data, we have developed models that, with high accuracy, predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell-type-specific manner. Our results propose a novel paradigm for NFκB-mediated repression, whereby NFκB selectively redistributes cofactors from high-occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.

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“…They are modular proteins, which contain small domains that serve as docking platforms for the Sin3-HDAC complex, HATs, WW- and WD40 domain proteins, histone methyltransferases and chromodomain reader molecules [103, 107, 109–112]. In addition, these proteins also heterodimerize with NFκB and PPARγ, which bring additional complexes along for regulatory purposes [102, 113, 114]. For instance, by coupling to the HP1-SUV39H1 as well as to the Sin3-HDAC pathway, these proteins are able to mark the promoters of metabolic gene networks to affect cell survival and growth [101].…”

Section: Epigenetics Opens a New Era For Pancreatic Cancer Markers Anmentioning

confidence: 99%

The Triple-Code Model for Pancreatic Cancer

Lomberk¹,

Urrutia²

2015

Surgical Clinics of North America

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Pancreatic adenocarcinoma (PDAC) is a lethal and painful disease, which has become one of the most frequent causes of death by malignant diseases around the world. Unfortunately, for the most part, this disease remains incurable. Significant advances in the field of genetics, particularly during the last two decades, has led to the proposal of a progression model, by which this cancer evolves by the accumulation of mutations and deletions in key oncogenes and tumor suppressor genes. This model has been remarkably useful for the development of tumor markers as well as elegant animal models. In spite of these strengths, this model does not take into consideration concepts and methodologies that have been derived from the field of epigenetics nor studies in the field of nuclear structure and function. Since our laboratory has been long been an advocate of these changes as critical for the pathobiology of pancreatic cancer, in this article, we describe an updated, more comprehensive model, which includes these concepts. With the widespread utilization of next generation sequencing for identifying both genetic and epigenetic changes genome-wide, we believe that the framework of this model will help to further identify and validate not only more but better markers for pancreatic cancer. In addition, as opposed to genetic changes, epigenetic alterations are amenable to pharmacological manipulations, consequently the familiarization with this model will help to better understand the potential beneficial effects of this type of therapy for this disease. Thus, we are optimistic that this new integrated paradigm will contribute to advance this field of research not only from a mechanistic point of view, but also from a translational one.

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Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

Cited by 134 publications

References 85 publications

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers

The Triple-Code Model for Pancreatic Cancer

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