Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers

Abstract

Long-term exposure to peroxisome proliferator-activated receptor g (PPARg) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARg binding, leading to the formation of PPARg ''superenhancers'' that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARg and appears to cooperate with PPARg in a feed-forward manner to activate and maintain the brite-selective gene program.

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

“…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.…”

“…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).…”

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

“…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).…”

The Triple-Code Model for Pancreatic Cancer

“…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].…”