SB, Massachusetts Institute of Technology 1984
MD, PhD John Hopkins University 1992
Tinman Article in MUSC Progress Notes
The Lee laboratory focus on early heart development, particularly as it pertains to mechanisms causing congenital heart disease in humans.
We currently study the genetic pathways leading to and emanating from the early cardiac transcription factor, Nkx2-5, which has long been associated with congenital anomalies. Alteration of Nkx2-5 expression levels has a profound effect on development of the Second Heart Field (SHF), a distinct set of heart precursors which gives rise to both outflow tract (OFT) and right ventricle at the aortic pole of the embryonic heart. Disruption of Nkx2-5 expression in mouse models results in a spectrum of defects from severe hypoplasia of OFT and right ventricle to milder OFT rotation or alignment defects such as double outlet right ventricle (DORV). Missense mutations of Nkx2-5 in human kindreds are similarly associated with OFT defects like DORV and Tetralogy of Fallot. This represents a significant clinical association: of the congenital heart anomalies that occur in nearly one percent of all human live births, nearly one-third involve the OFT and associated aorta and pulmonary artery.
Our efforts are directed towards two main pathways to discovery:
1. Identification of the direct downstream gene targets of the Nkx2-5 transcription factor in cells of the second heart field.
This effort utilizes a combination of SHF-specific microarray expression analysis and genome-wide association analysis (GWAS) using chromatin immunoprecipitation or ChIP.
2. Delineation of the transcriptional regulation of Nkx2-5 in second heart field.
This effort utilizes a comparative analysis of mammalian and avian second heart field enhancers of Nkx2-5 from mouse and chick Nkx2-5 genes.
Experimental Systems in Use
- Clark, C. D., Zhang, B., Lee, B., Evans, S. I., Lassar, A. B., and Lee, K. H. (2012) Evolutionary Conservation of Nkx2.5 Autoregulation in the Second Heart Field. Dev. Biol. 374 (1):198-209. PMCID: PMC3549048
- Brody, M. J., Mysliwiec, M. R., Kim, T. G., Carlson, C. D., Cho, E. Lee, K. H. and Lee, Y. S. (2013) Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. J. Molec. Cell Cardiol. S0022-2828 (13): 198-203. PMID: 23751912.
- Barth, J.L., Clark, C.D., Fresco, V.M., Knoll, E.P., Lee, B., Argraves, W.S., and Lee, K.H. (2010). Jarid2 is among a set of genes differentially regulated by Nkx2.5 during outflow tract morphogenesis. Dev Dyn 239, 2024-2033.
- Ikeda, S., He, A., Kong, S.W., Lu, J., Bejar, R., Bodyank, N., Lee, K.H., Ma, Q., Kang, P., Golub, T., and Pu,
W.T. (2009) microRNA-1 attenuates cardiomyocyte hypertrophy by negatively regulating calmodulin and
Mef2a. Mol. Cell. Biol. 29(8):2193-204.
- Rivera-Feliciano, J., Lee, K.H., Kong, S.W., Ma, Q., Springer, Z., Izumo, S., Tabin, C.J. and Pu, W.T. (2006) Development of heart valves requires Gata4 expression in endocardium derived cells. Development 133(18): 3607-18.
- Lee, K. H., Evans, S., Ruan, T. Y., and Lassar, A. B. (2004). Smad-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA-4,-5,-6 dependent chick Nkx-2.5 enhancer. Development 131: 4709-4723.
- Miller, C. T., Schilling, T. F., Lee, K. H., Parker, J., and Kimmel, C. B. (2000) sucker encodes a zebrafish Endothelin-1 required for ventral pharyngeal arch development. Development 127: 3815-3813.
- Angelo, S., Lohr, J., Lee, K. H., Ticho, B., Breitbart, R., Hill, S., Yost, J., and Srivastava, D. (2000). Conservation of sequence and expression of Xenopus and zebrafish dHAND during cardiac, branchial arch and lateral mesoderm development. Mech. Dev. 95: 239-243.