The Pitx2 homeodomain transcription factor is a central transcriptional regulator in left right asymmetry that functions within the heart to control cardiac morphogenesis. It is now clear that Pitx2 is fundamentally connected to AF although the basis for this connection remains obscure. The first evidence for the Pitx2-AF link was made in a Genome Wide Association Study (GWAS) implicating a region of chromosome 4q25 in early onset familial AF. Pitx2 was the gene in closest proximity to the disease associated single nucleotide polymorphism (SNP). AF patients with the 4q25 SNP were free of hypertension, diabetes and valve defects. Moreover, patients with the 4q25 SNP were more prone to cardioembolic stroke adding further urgency to gain insight to the underlying molecular mechanisms associated with the 4q25 SNP. We were the first group to report that Pitx2 heterozygous mice were predisposed to AF indicating that reduced levels of Pitx2 led to AF. Three different groups have subsequently replicated our findings. Because of its critical role in AF, we hypothesized that genome wide analysis of Pitx2 transcriptional target genes would provide novel and fundamentally important insight into the molecular mechanisms for AF in the Pitx2 happloinsufficient state. Our preliminary Chromatin Immuno Precipitation (ChIP) sequence (seq) data indicate that Pitx2 directly binds to a number of genes that have been implicated in AF and also genes that respond to reactive oxygen species. Moreover, our preliminary data indicate that Pitx2 may be regulate by the Hippo pathway, an essential cardiac regenerative pathway. There is poor understanding of the genetic mechanisms underlying AF. New genetic insights will be critical for diagnostic testing and family counseling in the future. Moreover, an in depth knowledge of genetics of AF will provide critical resources for patient management as human genome sequencing becomes more commonplace. Finally, there is the long term goal to develop novel therapeutic strategies based on solid scientific information that will come from work in model organisms and human genetics.
Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia in the human population, is associated with a high incidence of stroke leading to substantial disability, suffering, and enormous health care costs. Because AF prevalence increases with age, affecting approximately 5% of the human population over 65, the incidence of AF will increase and continue to be a large public burden. In this proposal, we will perform an in depth study of genes that are important in AF.
|Scavuzzo, Marissa A; Hill, Matthew C; Chmielowiec, Jolanta et al. (2018) Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis. Nat Commun 9:3356|
|Xiao, Yang; Hill, Matthew C; Zhang, Min et al. (2018) Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development. Dev Cell 45:153-169.e6|
|Li, Lele; Tao, Ge; Hill, Matthew C et al. (2018) Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition. Development 145:|
|Wang, J; Martin, J F (2017) Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development. J Dent Res 96:1229-1237|
|van Vliet, Patrick P; Lin, Lizhu; Boogerd, Cornelis J et al. (2017) Tissue specific requirements for WNT11 in developing outflow tract and dorsal mesenchymal protrusion. Dev Biol 429:249-259|
|Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686|
|Martin, James F; Perin, Emerson C; Willerson, James T (2017) Direct Stimulation of Cardiogenesis: A New Paradigm for Treating Heart Disease. Circ Res 121:13-15|
|Jarrett, Kelsey E; Lee, Ciaran M; Yeh, Yi-Hsien et al. (2017) Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci Rep 7:44624|
|Leach, John P; Heallen, Todd; Zhang, Min et al. (2017) Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550:260-264|
|Morikawa, Yuka; Heallen, Todd; Leach, John et al. (2017) Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547:227-231|
Showing the most recent 10 out of 27 publications