Gene Regulatory Events Underlying Cardiovascular Metabolism
The lab focuses on the gene regulatory events underlying cardiovascular metabolism.
The heart and skeletal muscle are highly metabolically active tissues. Their rates of energy consumption, choice of substrates, and method of catabolism can vary widely. Aberrant generation or use of energy in these tissues can lead to various diseases, including myopathies and heart failure. Conversely, optimal handling of energy improves exercise performance, and can have beneficial impact on chronic diseases like diabetes.
Energy in the cell is most efficiently generated by complete oxidation, in the mitochondria, of substrates like sugars and fat. ATP is abundantly generated in the process, while free oxygen is obligatorily reduced to water. The generation and regulation of mitochondria is complex and highly regulated. Importantly, the proper delivery of oxygen and nutrients must also be closely coordinated with mitochondrial function. Accordingly, highly oxidative tissues are almost invariably also highly vascular. The gene regulatory networks underlying these processes are only beginning to be understood.
Transcriptional co-activators are proteins that interact with DNA-bound transcription factors to regulate gene expression. It is likely that most if not all transcription factors require co-activators. Certain co-activators are highly regulated and integrate extracellular cues to affect gene regulation. Probably the best example of this is the small family of PGC-1 co-activators (PGC-1α, PGC-1β, and PRC). The PGC-1's interact with a number of chromatin-bound transcription factors, including most nuclear receptors. The PGC-1's assist in the activation of the basal transcriptional machinery, including the mediator complex; assist in the recruitment of chromatin-modifying enzymes such as histone acetylases like p300; and help coordinate transcription with the splicing machinery. The result is robust gene induction.
The PGC-1's control various biological pathways in different tissues. Common to these functions, is the regulation of mitochondrial biogenesis and activity. The exogenous addition of PGC-1's is sufficient to drive the formation of fully functional mitochondria, both in cell culture and in vivo. Conversely, deletion of either PGC-1α or β leads to mitochondrial defects in numerous tissues. To do this, the PGC-1's must coordinate the activation of 100's of genes, both on the nuclear and mitochondrial genomes. This occurs in part through co-activation of the nuclear respiratory factors (NRF-1 and 2), the orphan nuclear receptors ERRα and γ, and likely a number of other transcription factors.
We have recently shown that PGC-1α also regulates angiogenesis. PGC-1α regulates a broad angiogenic program, including the expression of VEGF and a number of other angiogenic factors, leading to a dramatic increase in vasculature density in PGC-1α transgenic animals. The induction of VEGF by PGC-1α requires the co-activation of ERRα on conserved binding sites found in the promoter and in a newly identified enhancer within the first intron of the VEGF gene. Hence, PGC-1α and ERRα, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates.
In addition, PGC-1α also appears to play a specific role in the response to ischemia. PGC-1α is induced by withdrawal of nutrients and oxygen, and full induction of VEGF by these conditions requires PGC-1α. PGC-1α -/- mice show a striking failure to normally reconstitute blood flow to the limb after an ischemic insult. Conversely, transgenic expression of PGC-1α in skeletal muscle is protective. Hence, PGC-1α plays a critical role in the regulation of angiogenesis, both in health and disease.
The lab currently focuses on addressing a number of questions:
- What is the role of PGC-1 coactivators in regulating angiogenesis in various physiological and pathophysiological contexts?
- What is the role of PGC-1 coactivators in regulating cardiac and skeletal muscle metabolism?
- How are genes of oxidative phosphorylation and mitochondrial biology regulated during hypoxia and ischemia?
- What transcriptional networks regulate metabolic changes and angiogenesis in cardiac and skeletal muscle?
We take a multidisciplinary approach to these questions, ranging from molecular biology and high-throughput genomics to cell biology and mouse physiology. Our goal is to understand the gene regulatory events that underlie physiological and pathological metabolic adaptations in both heart and skeletal muscle.