A Cardiac MicroRNA Governs Systemic Energy Homeostasis by Regulation of MED13

SummaryObesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.PaperCli

Zero-Shot Event Detection by Multimodal Distributional Semantic Embedding of Videos

We propose a new zero-shot Event Detection method by Multi-modal Distributional Semantic embedding of videos. Our model embeds object and action concepts as well as other available modalities from videos into a distributional semantic space. To our knowledge, this is the first Zero-Shot event detection model that is built on top of distributional semantics and extends it in the following directions: (a) semantic embedding of multimodal information in videos (with focus on the visual modalities), (b) automatically determining relevance of concepts/attributes to a free text query, which could be useful for other applications, and (c) retrieving videos by free text event query (e.g., "changing a vehicle tire") based on their content. We embed videos into a distributional semantic space and then measure the similarity between videos and the event query in a free text form. We validated our method on the large TRECVID MED (Multimedia Event Detection) challenge. Using only the event title as a query, our method outperformed the state-of-the-art that uses big descriptions from 12.6% to 13.5% with MAP metric and 0.73 to 0.83 with ROC-AUC metric. It is also an order of magnitude faster.Comment: To appear in AAAI 201

Smad7:β-catenin Complex Regulates Myogenic Gene Transcription

Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-β signaling. Here further characterization of the myogenic function of Smad7 revealed β-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of β-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and β-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and β-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the β-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished β-catenin function, indicating that SID functions as a trans dominant-negative regulator of β-catenin activity. β-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-β-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration.York University Librarie

Med13 Degradation Defines a New Receptor-Mediated Autophagy Pathway Activated by Nutrient Deprivation

Cells are exposed to an enormous amount of diverse extracellular cues but have a limited arsenal of weapons for protecting and maintaining homeostasis. To overcome these restrictions, nature has engineered proteins that have multiple functions. The pleiotropy of using one protein to carry out a variety of functions allows cells to rapidly execute tailored responses to a diverse set of signals. The Cdk8 kinase module (CKM) is a conserved detachable unit of the Mediator complex predominantly known for its role in transcriptional regulation. The CKM is composed of four proteins, the scaffolding proteins Med13 and Med12, as well as the non-canonical cyclin, cyclin C, and its cognate kinase, Cdk8. Previously it has been shown that cyclin C is a multifunctional protein that performs transcriptional and stress-induced roles at the mitochondria. The localization, post-translational modifications, and different functional domains of cyclin C regulate these separate functions. Here we show that Med13 also has dual roles in regulating stress response following nutrient depletion. In physiological conditions, Med13 works within the CKM to negatively regulate the expression of autophagy genes (ATG). Following starvation, this repression is relieved by Snx4-assisted autophagy of Med13. Moreover, we identified Ksp1 to be the autophagic receptor protein for this novel autophagy pathway. Structural analysis by others showed that Med13 has an RNA binding region. Consistent with this, we showed that once in the cytosol, Med13 localizes to ribonucleoprotein granules known as processing bodies (P-bodies) which function in mRNA silencing, decay, and storage. In addition, we show that Med13, together with Ksp1 and Snx4, are required for the autophagic degradation of conserved P-body proteins following stress. These results illustrate the day and night jobs of Med13 in response to starvation stress. Lastly, we illustrate that the regulation of autophagy by the CKM is evolutionarily conserved. Here we show that cyclin C promotes autophagy and proteasome activity in the murine pancreatic cancer model. Collectively, these studies demonstrate the multifunctionality and conservation of the CKM in stress response

The Involvement of Ubiquitin in Med13 Cyclin C Degradation Following Cellular Stress

The Cdk8 Kinase Module is a dissociable regulator of cellular stress response genes, with degradation of its components Med13 and cyclin C eventually determining cell fate decisions such as engaging cell survival or cell death mechanisms. We aimed to explore the roles of ubiquitin in degradation of the Cdk8 Kinase Module following nitrogen starvation, with respect to the potential involvement of deubiquitinating enzyme Doa4, lysine linkage at position K63, and E2 ubiquitin conjugating enzymes Ubc4 and Ubc5. We utilized Western blot analysis to observe nitrogen starvation-induced degradation of Med13-HA in wild-type, doa4 mutant, and K63R yeast strains; degradation of cyclin C-MYC in wild-type and K63R strains; and Atg8-GFP activity in wild-type and ubc4/5 mutant strains, with Pgk1-GFP as a loading control. Results indicated that Med13 was degraded in doa4 mutant and K63R yeast strains, while cyclin C was stabilized in K63R strains. Additionally, GFP was cleaved from Atg8 in both wild-type and ubc4/5 mutant strains. We therefore determined that Med13 degradation does not require Doa4 or K63, and that Ubc4 and Ubc5 are specific to Med13 autophagy. However, K63 ubiquitin linkage is implicated in cyclin C degradation following nitrogen starvation, warranting further investigation

Mediator complex component MED13 regulates zygotic genome activation and is required for postimplantation development in the mouse

Understanding factors that regulate zygotic genome activation (ZGA) is critical for determining how cells are reprogrammed to become totipotent or pluripotent. There is limited information regarding how this process occurs physiologically in early mammalian embryos. Here, we identify a mediator complex subunit, MED13, as translated during mouse oocyte maturation and transcribed early from the zygotic genome. Knockdown and conditional knockout approaches demonstrate that MED13 is essential for ZGA in the mouse, in part by regulating expression of the embryo-specific chromatin remodeling complex, esBAF. The role of MED13 in ZGA is mediated in part by interactions with E2F transcription factors. In addition to MED13, its paralog, MED13L, is required for successful preimplantation embryo development. MED13L partially compensates for loss of MED13 function in preimplantation knockout embryos, but postimplantation development is not rescued by MED13L. Our data demonstrate an essential role for MED13 in supporting chromatin reprogramming and directed transcription of essential genes during ZGA.Fil: Miao, Yi Liang. National Institutes of Health; Estados UnidosFil: Gambini, Andres. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zhang, Yingpei. National Institutes of Health; Estados UnidosFil: Padilla Banks, Elizabeth. National Institutes of Health; Estados UnidosFil: Jefferson, Wendy N.. National Institutes of Health; Estados UnidosFil: Bernhardt, Miranda L.. National Institutes of Health; Estados UnidosFil: Huang, Weichun. National Institutes of Health; Estados UnidosFil: Li, Leping. National Institutes of Health; Estados UnidosFil: Williams, Carmen J.. National Institutes of Health; Estados Unido

Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells

In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by beta-catenin, which has previously been shown to associate with MED12. Importantly, beta-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.Peer reviewe

Snf1 Dependent Destruction of Med13 is Required for Programmed Cell Death Following Oxidative Stress in Yeast

All eukaryotic cells, when faced with unfavorable environmental conditions, have to decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction1, which thereafter releases cyclin Ci nto the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation and programmed cell death2. This suggests a model in which oxidative stress mediated destruction o fMed13 represents a key molecular switch which commits the cell to programmed cell death. Thus it is important to decipher the precise molecular mechanisms that control Med13 destruction following exposure to oxidative stress

Strategies for Searching Video Content with Text Queries or Video Examples

The large number of user-generated videos uploaded on to the Internet everyday has led to many commercial video search engines, which mainly rely on text metadata for search. However, metadata is often lacking for user-generated videos, thus these videos are unsearchable by current search engines. Therefore, content-based video retrieval (CBVR) tackles this metadata-scarcity problem by directly analyzing the visual and audio streams of each video. CBVR encompasses multiple research topics, including low-level feature design, feature fusion, semantic detector training and video search/reranking. We present novel strategies in these topics to enhance CBVR in both accuracy and speed under different query inputs, including pure textual queries and query by video examples. Our proposed strategies have been incorporated into our submission for the TRECVID 2014 Multimedia Event Detection evaluation, where our system outperformed other submissions in both text queries and video example queries, thus demonstrating the effectiveness of our proposed approaches

Regulation of metabolism by miR-378

The present invention provides a method of regulating fatty acid metabolism in a cell by contacting the cell with a modulator of miR-378 and/or miR-378* activity or expression. The present invention also provides a method of treating or preventing a metabolic disorder, such as obesity, diabetes, or metabolic syndrome, in a subject by administering to the subject an inhibitor of miR-378 and/or miR-378* expression or activity. Methods of treating or preventing pathologic cardiac hypertrophy, cardiac remodeling, myocardial infarction, or heart failure in a subject by inhibiting the expression or activity of miR-378 and/or miR-378* in a subject are also disclosed.Board of Regents, University of Texas Syste