Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma‐initiating cells

Dali, Rola; Verginelli, Federica; Pramatarova, Albéna; Sladek, Robert; Stifani, Stefano

doi:10.1002/1878-0261.12168

“…The genomic distribution of TLE3 mapped principally to distal regions of the mouse genome ( Fig. 5C), an observation that is consistent with the TLE/Groucho family being located primarily at enhancers (Chambers et al 2017;Dali et al 2018). There was nearly equal distribution of binding upstream of and downstream from the transcriptional start site (TSS) (Supplemental Fig.…”

Section: Tle3 Promotes Diet-induced Weight Gain and Glucose Intolerancesupporting

confidence: 67%

Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Pearson

¹

,

Loft

²

,

Rajbhandari

³

et al. 2019

View full text Add to dashboard Cite

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

show abstract

“…The genomic distribution of TLE3 mapped principally to distal regions of the mouse genome ( Figure 5C), an observation that is consistent with the TLE/Groucho family being located primarily at enhancers (37,38). There was nearly equal distribution of binding upstream and downstream of the transcriptional start site (TSS) ( Figure S5A).…”

Section: Genome-wide Analysis Reveals Preferential Association Of Tlesupporting

confidence: 57%

Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Pearson

¹

,

Loft

²

,

Rahbhandari

³

et al. 2018

Preprint

View full text Add to dashboard Cite

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age-and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control.Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes. the presence of these thermogenic tissues are inversely related to metabolic disorders and obesity (7, 21), understanding the regulatory mechanisms that govern the development and activity of thermogenic adipocytes has become an area of intense therapeutic interest.All adipocyte subtypes require peroxisome proliferator-activated receptor gamma (PPARg), which is necessary and sufficient to drive adipocyte differentiation (22). A prior genomewide survey of PPARg binding profiles from primary cells isolated from three separate tissues (iWAT, eWAT, and BAT) differentiated in vitro showed an overlap in binding and similar intensities at the majority of PPARg binding sites (23). However, this study also revealed a subset of depotspecific binding sites that correlated well with depot-specific gene expression (23). These findings suggested that PPARg likely works in concert with other transcription factors and transcriptional co-regulators to regulate cell-type specific gene expression, although the identities of these auxiliary factors remain to be fully elucidated.Among the transcription factors known to work in concert with PPARg to determine adipocyte identity are those of the early B-cell factor (EBF) family. Both EBF1 and EBF2 participate in early adipogenesis (24, 25), and it has recently been demonstrated that they also play important roles in differentiated adipocytes. EBF1 positively regulates insulin-stimulated glucose uptake and lipogenesis (26), (27), while EBF2 is selectively expressed in brown adipocytes and facilitates the binding of PPARg to brown fat-specific genes to promote thermogenesis (28)-(29). The EBF DNA binding motif associates with BAT-specific PPARg binding sites (28) and enhances expression of genes important for mitochondrial function (30).The transducin-like enhancer of split (TLE) protein fam...

show abstract

“…Notably, several R-CIS are located on chromosomes 4 and 15, the locations of the T2/Onc2 and T2/Onc concatemers, respectively. Although local hopping may account for bias toward genes on these chromosomes, several are implicated in cancer, including Tle1 and Ptprd (35,36). In addition, these concatemers have been previously used to identify R-CIS in osteosarcoma, and only 1 R-CIS gene was common to both studies (Cdkn2a; Supplementary Table S9; ref.…”

Section: Discussionmentioning

confidence: 99%

Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Beckmann

¹

,

Larson

²

,

Larsson

³

et al. 2019

View full text Add to dashboard Cite

Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arh-gap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

show abstract

Characterization of a FOXG1:TLE1 transcriptional network in glioblastoma‐initiating cells

Cited by 24 publications

References 59 publications

Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Contact Info

Product

Resources

About