In broad terms, my lab is interested in the transcriptional control of cellular proliferation and how these controls are subverted in human malignancy. We are currently focused on understanding how cells communicate information about their metabolic state to the nucleus to ultimately drive adaptive changes in gene expression. Furthermore, we are interested in how these metabolic signals coordinate with the signals that control cell growth, division, and death. We use a wide array of approaches from biochemistry to genomics and studies in both worm and mouse models to examine these questions. Our efforts are focused in two main areas:

  • The communication between mitochondria and the nucleus
  • The mechanisms of transcriptional repression

A Parallel Myc-like Network

Myc and Max localize primarily to the nucleus and the activity of the complex is controlled primarily by the availability of the short-lived Myc protein. By contrast, MondoA and Mlx are both stable proteins that localize to the cytoplasm. As such, their subcellular distribution, which is mediated by interactions with the nuclear export factor CRM1 and members of the 14.3.3 family, controls their nuclear function as transcriptional activators. Surprisingly, MondoA localizes to the outer mitochondrial membrane. This finding coupled with our discovery that several key glycolytic enzymes are transcriptional targets of MondoA:Mlx, suggests that MondoA:Mlx heterocomplexes sense information about intracellular energy status at the mitochondria and communicate that information to the nucleus ultimately driving adaptive changes in gene expression.

MondoA is a Metabolic Energy Sensor

Myc and Max localize primarily to the nucleus and the activity of the complex is controlled primarily by the availability of the short-lived Myc protein. By contrast, MondoA and Mlx are both stable proteins that localize to the cytoplasm. As such, their subcellular distribution, which is mediated by interactions with the nuclear export factor CRM1 and members of the 14.3.3 family, controls their nuclear function as transcriptional activators. Surprisingly, MondoA localizes to the outer mitochondrial membrane. This finding coupled with our discovery that several key glycolytic enzymes are transcriptional targets of MondoA:Mlx, suggests that MondoA:Mlx heterocomplexes sense information about intracellular energy status at the mitochondria and communicate that information to the nucleus ultimately driving adaptive changes in gene expression.

Mondo Function in Model Organisms

While tissue culture models of MondoA function are powerful, they do have their limitations. Therefore, we are also examining the function of Mondo orthologs in the mouse and in the nematode C. elegans. In the mouse system, we have generated a conditional allele of MondoA. We plan to knockout MondoA in the entire organism and in specific tissues to determine the role of MondoA in development and organismal energy homeostasis. In C. elegans, the "Myc"-like network is much simpler than in higher eukaryotes with clear Mondo, Mlx, Mad and Max orthologs. Surprisingly, there is no clear Myc ortholog in C. elegans. Our investigation of this simplified transcription factor network will afford us a better understanding of its biological role without the problems of genetic redundancy and compensation present when studying the network in higher eukaryotes.

Molecular Architecture of the mSin3A Corepressor Complex

Molecular architecture of the mSin3A corepressor complex was initially discovered as a corepressor for Mad1:Max heterodimers, and it was the first corepressor identified in mammalian systems. Our lab was among the first to show that mSin3A is present in cells as a large multiprotein complex and depends on associated histone deacetylases for its full corepressor function. This was the first description of how histone deacetylases are targeted to promoter regions. We have gone on to identify a number of proteins, such as MRG15, Pf1 and TLE1, which interact with the mSin3A complex in substoichiometric amounts. We have also identified SAP130, SAP180, and mSDS3 as core stoichiometric members of the mSin3A complex. We are now determining how each of these mSin3A-associated factors contribute to the assembly, targeting, and regulation of the mSin3A complex.

News & Blog

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Huntsman Cancer Institute Researchers Share Expertise at National Cancer Meeting
Health Care Transformation, Clinical, Research, Education
Apr 11, 2017

Huntsman Cancer Institute Researchers Share Expertise at National Cancer Meeting

Huntsman Cancer Institute,

More than 20 researchers from Huntsman Cancer Institute (HCI) at the University of Utah made their mark on the American Association of Cancer Research (AACR) Annual Meeting this year. Held in Washington, D.C., the convention drew more than 21,500 cancer researchers from all over the world. Scientists attended sessions on topics from immunotherapy to precision medicine. About 15 researchers from HCI presented posters in the main conference hall, on a wide range of topics. ... Read More

Characterization of the Nutrient Needs of Triple Negative Breast Cancer Leads to the Identification of a Molecular Signature for Cancer Outcomes
Health Care Transformation, Research, Education
Apr 13, 2015

Characterization of the Nutrient Needs of Triple Negative Breast Cancer Leads to the Identification of a Molecular Signature for Cancer Outcomes

Huntsman Cancer Institute,

Compared to other types of breast cancer, triple negative breast cancers are often more aggressive and have fewer treatment options. In a new study published in the journal Proceedings of the National Academy of Sciences (PNAS), researchers at Huntsman Cancer Institute and the University of Utah have identified a molecular mechanism that triple negative breast cancer cells use to survive and grow.... Read More

Principle Investigator

Donald E Ayer, PhD
Principal Investigator
don.ayer@hci.utah.edu

Cancer Center Bio