Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13

Carrera, Inés; Janody, Florence; Leeds, Nina B.; Duveau, Fabien; Treisman, Jessica E.

doi:10.1073/pnas.0709749105

Cited by 120 publications

(119 citation statements)

References 81 publications

(99 reference statements)

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“…Our findings reveal a close functional connection between MED13 and Arm, suggestive of the role of MED13 in Wg target gene expression. In fact, in the developing Drosophila eye and wing, MED13 and MED12 are essential for Wg target gene expression, and the MED13/MED12 complex physically interacts with Pygopus, a component of the Wg transcriptional complex (40). Furthermore, MED12 hypomorphic mutant mice are embryonic lethal with impaired expression of Wnt targets (41).…”

Section: Discussionmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.O besity is a systemic disorder caused by an energy imbalance in which energy input exceeds energy utilization, resulting in accumulation of excess body fat. Muscle plays a central role in systemic energy homeostasis by consuming nutrients and signaling in an endocrine manner to other tissues (1-3). Thus, there has been intense interest in identifying secreted factors from muscle that modulate the function of adipose tissue.Previously, we reported that cardiac deletion of MED13, a subunit of the Mediator complex, increases susceptibility to obesity in mice whereas cardiac overexpression of MED13 confers a lean phenotype (4), revealing an unforeseen function of the heart as a systemic regulator of energy homeostasis. The Mediator is a conserved multisubunit complex that mediates the interaction between RNA polymerase II and transcription factors and therefore governs transcription in all eukaryotes (5). MED13 and MED12 are among four subunits of the auxiliary kinase module, which confers additional regulatory functions to the Mediator complex (6). Expression profiling of yeast mutants or gene-depleted Drosophila cell lines revealed a close correlation between the gene-expression programs controlled by MED13 and MED12, suggesting their concerted actions in gene regulation (7,8).Drosophila provides a powerful model system for the genetic analysis of obesity (9-11). The processes that regulate energy homeostasis, such as energy storage and mobilization of fat in adipose tissue of the fat bo...

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Section: Discussionmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…This is proposed to promote Wnt target activation by binding the mediator complex subunits Med12 and Med13 (Fig. 5) (Carrera et al 2008), as well as the TFIID complex subunit TAF4 (Wright and Tjian 2009). In addition, Pygo's PHD domain can bind histone H3 methylated at lysine 4 (H3K4me).…”

Section: Into the Nucleus-target Gene Regulation By Bcat/armmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

275

259

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One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

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“…26,30,34,35 Still, the function of the Cdk8 module is under debate since its subunits have been implicated in both, transcriptional activation and repression. 29,[36][37][38][39][40] In particular, Med12 was shown to operate as a signaling pathway hub in C. elegans suggesting a function in different cellular pathways. 41 Furthermore, Med12 is involved in the Polycomb-mediated repression of Hox genes in D. melanogaster contrasting a general role in transcriptional activation.…”

Section: Introductionmentioning

confidence: 99%

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

et al. 2016

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Mediator is considered an enhancer of RNA-Polymerase II dependent transcription but its function and regulation in pluripotent mouse embryonic stem cells (mESCs) remains unresolved. One means of controlling the function of Mediator is provided by the binding of the Cdk8 module (Med12, Cdk8, Ccnc and Med13) to the core Mediator. Here we report that Med12 operates together with PRC1 to silence key developmental genes in pluripotency. At the molecular level, while PRC1 represses genes it is also required to assemble ncRNA containing Med12-Mediator complexes. In the course of cellular differentiation the H2A ubiquitin binding protein Zrf1 abrogates PRC1-Med12 binding and facilitates the association of Cdk8 with Mediator. This remodeling of Mediator-associated protein complexes converts Mediator from a transcriptional repressor to a transcriptional enhancer, which then mediates ncRNA-dependent activation of Polycomb target genes. Altogether, our data reveal how the interplay of PRC1, ncRNA and Mediator complexes controls pluripotency and cellular differentiation.

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Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13

Cited by 120 publications

References 81 publications

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Wnt Signaling from Development to Disease: Insights from Model Systems

Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation

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