Cardiovascular disease is the most common cause of mortality in adults, and congenital heart defects are the most common form of birth defects in the US. AMP-activated protein kinase (AMPK) is a master regulator of energy balance and homeostasis and plays a central role in the switch from fatty acids to glycolysis during cardiac hypertrophy and heart failure. AMPKa2 is the predominant isoform ofthe catalytic subunit expressed in the heart and is encoded by the Prkaa2 gene. Although AMPK and its role in metabolism and heart failure have been extensively studied, the transcripfional control ofthe genes encoding AMPK subunits is completely unknown. The MADS box transcription factor MEF2C is required for cardiac development and functions as a signal responsive transcription factor that interacts with a variety of cofactors to either negatively or positively regulate transcription. The most potent transcriptional coactivator for MEF2C is the SAP domain transcripfional regulator Myocardin. MEF2C specifically interacts with Myocardin-93S, which is highly enriched in the heart, yet the transcripfional targets and mechanisms of synergy facilitated by the Myocardin-MEF2 complex have not been identified. Preliminary studies found that the Prkaa2 gene is a direct transcripfional target ofthe MEF2C-Myocardin complex via a novel cardiac- specific enhancer. This enhancer contains two bona fide MEF2 binding sites that function together in a multiplicative fashion in response to Myocardin-93S and MEF2C. Although transcripfional synergy is frequently observed in many contexts and is a well-described phenomenon, the role of cis-acting elements, their position, spacing, and sequence in facilitating synergy have been far less well described. Using transgenic mouse, cell culture, biochemical, and mass spectrometry approaches, this work will define determinants of MEF2-Myocardin transcripfional synergy, will identify additional interaction partners for MEF2C and Myocardin through interactome mapping, and will identify in vivo targets ofthe Myocardin-MEF2 complex. This work will also determine the upstream regulation of Prkaa2 for the first time. This work may provide additional strategies for manipulating AMPK expression during heart failure.
Cardiovascular disease is the most common cause of mortality in adults, and congenital heart defects are the most common form of birth defects in the US. AMPK controls energy balance in the heart and the switch from fatty acid to glucose metabolism during heart failure. This work will define how the gene encoding the regulatory subunit of AMPK is controlled and may provide strategies for manipulating this central regulator of metabolism during heart failure. This work will also define basic mechanisms of gene activation.
|Miyaoka, Yuichiro; Chan, Amanda H; Judge, Luke M et al. (2014) Isolation of single-base genome-edited human iPS cells without antibiotic selection. Nat Methods 11:291-3|
|Spencer, C Ian; Baba, Shiro; Nakamura, Kenta et al. (2014) Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports 3:269-81|
|Ang, Yen-Sin; Srivastava, Deepak (2014) Oxygen: double-edged sword in cardiac function and repair. Circ Res 115:824-5|
|Hua, Lisa L; Vedantham, Vasanth; Barnes, Ralston M et al. (2014) Specification of the mouse cardiac conduction system in the absence of Endothelin signaling. Dev Biol 393:245-54|
|Ehlers, Melissa L; Celona, Barbara; Black, Brian L (2014) NFATc1 controls skeletal muscle fiber type and is a negative regulator of MyoD activity. Cell Rep 8:1639-48|
|Srivastava, Deepak; Heidersbach, Amy J (2013) Small solutions to big problems: microRNAs for cardiac regeneration. Circ Res 112:1412-4|
|Conklin, Bruce R (2013) Sculpting genomes with a hammer and chisel. Nat Methods 10:839-40|
|Srivastava, Deepak; Berry, Emily C (2013) Cardiac reprogramming: from mouse toward man. Curr Opin Genet Dev 23:574-8|
|Spindler, Matthew J; Burmeister, Brian T; Huang, Yu et al. (2013) AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to *-adrenergic-induced cardiac hypertrophy. PLoS One 8:e62705|
|Cheng, Paul; Andersen, Peter; Hassel, David et al. (2013) Fibronectin mediates mesendodermal cell fate decisions. Development 140:2587-96|
Showing the most recent 10 out of 33 publications