The Mediator is universally required for Polymerase II-dependent transcription, but some Mediator subunits affect specific gene sets and selectively implement biological programs. This is exemplified by our research on MDT-15 and CDK-8, two subunits of the C. elegans Mediator complex. MDT-15 integrates the transcription of genes involved in lipid biology and in the response to nutrition-associated stresses (fasting, heavy metals, xenobiotic toxins, and oxidative stress). Thus, we hypothesize that MDT-15 is a key component in a conserved metabolic regulatory network, and that its orthologue MED15 may be involved in human metabolic conditions such as obesity and diabetes. CDK-8 is the kinase of the Mediator complex, and it plays important roles during C. elegans development and differentiation. Intriguingly, its human ortholog CDK8 is an oncogene, but its normal function in development and physiology remains poorly understood. Our current projects address various elements of MDT-15 and CDK-8 function in C. elegans or mice.
1. MDT-15 driven metabolic homeostasis: MDT-15 is required to maintain metabolic homeostasis in C. elegans, but how altered lipid balance affects organelle, cellular, and organismal function remains poorly understood. Our experiments aim to delineate the consequence of lipid imbalances in worms lacking mdt-15, and how lipid metabolism and oxidative stress responses impinge on organismal health and aging.
2. MDT-15 interacting factors and molecular determinants: MDT-15 is the centre of a regulatory network that includes many Nuclear Hormone Receptors (NHRs). However, which, if any, part of MDT-15’s function these NHRs perform is unclear; moreover, we do not yet understand the molecular details of these interactions. Using advanced genetic, genomic, and biochemical methods, we are defining the individual roles of this network’s components.
3. Conservation of MED15 function in mammals: Given the metabolic regulatory role of MDT-15 in C. elegans, we are testing whether MED15, its mammalian homologue, performs similar functions. Using candidate and unbiased genomic approaches we aim to identify MED15's transcriptional targets and biological functions in cultured cells. Additionally, we have generated tissue-specific MED15 loss-of-function and we are now investigating their metabolic and developmental phenotypes.
4. Developmental regulation by CDK-8: In humans, CDK-8 is an oncogene but its role in normal development remains poorly understood. Benefitting from viable null or hypomorph mutations we have begun to dissect the role of CDK-8 and its associated module in C. elegans, and have found important roles in development and differentiation. In these contexts, CDK-8 engages several conserved signaling pathways, and our current research uses genetics and genomics to dissect the underlying molecular mechanism.