In July, 2003, I began working at the Indiana School of Medicine, as an Associate Professor, in the Department of Pediatrics, at the Herman B Wells Center for Pediatric Research. In July, 2009, I was promoted to Professor in the Departments of Pediatrics, Medical and Molecular Genetics, Anatomy & Cell Biology/Biochemistry.
Beginning in January, 2014, I was awarded the title of Carleton Buehl McCulloch Professor of Pediatrics.
For over 25 years, my independent career focus has been on gaining an understanding of the role that the bHLH Hand/Twist-family of proteins plays during heart development. My group has established that these factors have broad dimerization characteristics and that phosphoregulation of these proteins helps define bHLH partner choice. We have gone on to show that Hand/Twist-family gene dosage within a cell defines a bHLH code, which orchestrates cell specification, differentiation, and morphological patterning. This mechanism is directly involved in causing the human disease. We have discovered that bHLH partner choice pays a key role in the patterning of the face during embryonic development. Hand1 expression within the distal cap of the 1st pharyngeal arch is not necessary for normal craniofacial morphogenesis; however, when HAND1 dimer mutant knock in alleles are activated within the endogenous Hand1 expression domain, there is a pronounced mid face clefting that results from disruption of FGF and SHH signaling resulting in wide spread non-cell autonomous cell death within the forming 1st pharyngeal arch.
In other studies studies, we have discovered a number of Hand1 transcriptional enhancers that drive tissue specific expression within embryos. Hand1 transcriptional enhancers necessary and sufficient for recapitulating 1st pharyngeal arch expression, sympathetic nervous system, and left ventricle expression are published. Notable from this work, we show that HAND1 plays important roles in the cardiac conduction system morphogenesis, where Single Nucleotide Polymorphisms (SNPs) within the human HAND1 left ventricle enhancer are associated with abnormal cardiac conduction defects. We show that in gene edited mice which incorporate the human SNPs into the conserved mouse enhancer that transcription factor binding is altered and they present with abnormal cardiac conduction.
Our studies of HAND2 reveal that HAND2 lies downstream of NOTCH signaling within the developing endocardium and its endocardial loss of function results in tricuspid atresia. Single cell transcriptome analysis reveals that the shear stress pathway is impacted in Hand2 endocardial mutants. By looking at HAND2 DNA occupancy peaks within the endocardial genes regulated in our loss-of-function model, we have identified a number of novel endocardial transcriptional enhancers dependent on HAND2 function.
Our future efforts are focused on the discovery of novel Hand1 and Hand2 regulatory enhancers and identification of downstream targets to reveal the gene regulatory networks that drive embryogenesis.