Cell and Developmental Biology University of Michigan

Research

Mouse Developmental Genetics and Transcription; uses molecular genetics to understand the mechanisms underlying developmental determination during mammalian embryogenesis.

We employ molecular genetics to investigate the basic mechanisms underlying developmental determination during mammalian embryogenesis. Variation in the activity and abundance of transcription factors is widely acknowledged to be a regulatory nexus where signal cascades converge and are transduced into specific cellular responses. Regulation of the transcriptional apparatus is instructed through DNA:protein interactions mediated by specific transcription factors and accessory proteins. The underlying question we address is: how are tissues and organs generated, and how are they instructed to fulfil their differentiated fates? This most basic question can be dissected into components by addressing the multiple activities of individual transcription factor proteins and their genes.

How do tissue-restricted transcription factors mediate such an enormous diversity of potential responses, and how do their aberrant responses lead to human cancer and congenital disease? Our approach to these conundrums all employ mouse germ line gene manipulation. Our studies have led to fascinating insights into the developmental origin of, and elaboration of differentiated function in, the central and peripheral nervous system, the kidney, the cardiovascular system and blood. We also continue to explore the molecular basis of human beta-globin gene regulation, as it comprises one of the most sophisticated models for chromatin-modulated gene regulatory complexity.

Lab Members

• Tomonori Hosoya
  Research Investigator
• Kim-Chew Lim
  Research Assistant Professor
• Shuaiying Cui
  Research Fellow
• Bradley Godfrey
  Research Fellow
• Sakie Hosoya-Ohmura
  Research Fellow
• Chia-Jui Ku
  Research Fellow
• Lihong Shi
  Research Fellow
• Mary Herrmann
  Research Lab Technician
• Carmen Yu
  Research Lab Technician

Publications

Representative Publications

• Stalder, J., Groudine, M., Dodgson, J.B., Engel, J.D. and H. Weintraub (1980) Hb switching in chickens, Cell 19, 973-80.
• Stalder, J., Larsen, A., Groudine, M., Dolan, M., Engel, J.D. and H. Weintraub (1980) Tissue-specific DNA cleavages in the globin chromatin domain introduced by DNase I, Cell 20, 451-60.
• Choi, O.-R. and J.D. Engel (1986) A 3' enhancer is required for temporal and tissue-specific transcriptional activation of the chicken Β-globin gene, Nature 323, 731-34.
• Choi, O.-R. B. and J.D. Engel (1988) Developmental regulation of Β-globin gene switching, Cell 55, 17-26.
• Yamamoto, M., Ko, L.J., Leonard, M.W., Beug, H., Orkin, S.H. and J.D. Engel (1990) Activity and expression of the NF-E1 [GATA] multigene family, Genes Dev. 4, 1650-1662.
• Pandolfi, P.P., Roth, M.E., Karis, A., Leonard, M.W., Dzierzak, E., Grosveld, F., Engel, J. D., and M. H. Lindenbaum (1995) Targeted disruption of the Gata3 gene causes severe abnormalities in the nervous system and fetal liver haematopoiesis, Nature Gen. 11, 40-4.
• Bungert, J., Davé, U., Lim, K.-C., Lieuw, K. H., Shavit, J. A., Liu, Q. and J. D. Engel (1995) Synergistic regulation of human Β-globin gene switching by locus control region elements HS3 and HS4, Genes Dev. 9, 3083-96.
• Tanimoto, K., Bungert, J., Liu, Q., and J.D. Engel (1999) Effects of altered gene order or orientation of the locus control region on human Β-globin gene expression in mice, Nature 398, 344-349.
• Lim, K.-C., Lakshmanan, G., Crawford, S. E., Gu, Y., Grosveld, F. and J.D. Engel (2000) Gata3 gene ablation results in embryonic lethality as a consequence of sympathetic nervous system-specific catecholamine deficiency, Nature Gen. 25, 209-12.
• Tanimoto, K., Liu, Q., Grosveld, F., Bungert, J. and J.D. Engel (2000) Context-dependent EKLF responsiveness defines the developmental specificity of the human Β-globin gene in erythroid cells of YAC transgenic mice, Genes Dev. 14, 2778-94.
• Motohashi, H., Katsuoka, F., Shavit, J., Engel, J.D. and M. Yamamoto (2000) Positive or negative MARE-dependent transcriptional activation is determined by the abundance of small Maf proteins, Cell 103, 865-75.
• Tanabe, O., Katsuoka, F., Campbell, A.D., Song, W., Yamamoto, M., Tanimoto, K. and J.D. Engel (2002) A candidate erythroid embryonic/fetal globin gene repressor contains a nuclear orphan receptor TR2/TR4 heterodimer, EMBO J. 21, 3434-42.
• Suzuki, N., Ohneda, O., Minegishi, N., Nishikawa, M., Ohta, T., Takahashi, S., Engel, J.D. and M. Yamamoto (2006) Combinatorial Gata2 and ScaI expression defines hematopoietic stem cells in the bone marrow niche Proceedings of the National Academy of Sciences of the USA 103, 2202-7.
• Tanabe, O., Shen, Y., Liu, Q., Campbell, A., Kuroha, T., Yamamoto, M. and J.D. Engel (2007) The TR2 and TR4 Orphan Nuclear Receptors Repress Gata1 Transcription, Genes Dev. 21, 2832-44.
• Hosoya, T., Kuroha, T., Moriguchi, T., Cummings, D., Maillard, I., Lim, K.-C. and J.D. Engel (2009) GATA-3 is required for early T lineage progenitor development, Journal of Experimental Medicine 206, 2987-3000.
• Campbell, A., Cui, S., Shi, L., Urbonya, R., Mathias, A., Bradley, K., Bonsu, K.O., Douglas, R., Halford, B., Schmidt, L. Harro, D., Gaicherio, D., Tanimoto, K., Tanabe, O. and J.D. Engel (2011) Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes, Proceedings of the National Academy of Sciences USA 108, 18,808-13.
• Higgs, D.R., Engel, J.D. and G. Stamatoyannopoulos (2012) Thalasseaemia, Lancet 379, 373-83.
• Lim, K.-C, Brandt, W., Ku, C-J, Hosoya-Ohmura, S., Camper, S., Yamamoto, M., Hosoya, T. and J.D. Engel (2012) A Gata2 vascular endothelial enhancer is required for the generation of hematopoietic stem cells, J. Clinical Investigation, in press.