Bernard G. Forget

Professor of Medicine and Genetics

B.A. University of Montreal, Canada, 1959
M.D. McGill University, Montreal, Canada, 1963

Research Interests:

Molecular Genetics of Erythroid Cell Differentiation

The human red blood cell provides an excellent model system for the study of gene expression and the molecular basis of disease. In erythroid cells, a number of genes are expressed in a tissue-specific and developmentally regulated fashion. Furthermore, a number of inherited disorders of the red cell are due to mutations that result in abnormal expression of these specialized genes.

Current Research

My laboratory is involved in a research program concerned with the mechanisms of normal and abnormal human globin gene expression and the study of non-globin genes that are expressed during red blood cell differentiation. The work on globin genes is devoted to the investigation of molecular mechanisms involved in the neonatal switch from the synthesis of fetal to adult hemoglobin, with an emphasis on the study of cis- and trans-acting elements that control expression as well as naturally occuring mutations that can influence globin gene expression. A major research effort is also devoted to the study of the genes encoding the red cell membrane skeleton protein called spectrin. Spectrin genes are part of a multigene family, members of which are differentially expressed in different tissues. In addition, we are investigating the molecular basis of a number of genetic diseases of the red cell (hereditary hemolytic anemias) that are due to disorders of spectrin. The structure and function of the erythropoietin receptor gene is also being studied.

Our approach involves gene cloning, sequencing, and mapping. The cloned genes are then transferred into tissue culture cells or transgenic mice for analysis of gene transcription and posttranscriptional processing of nascent transcripts. The polymerase chain reaction (PCR) technique is used extensively for the amplification of genomic DNA or cDNA in the study of gene structure and identification of gene mutations. Finally, normal and mutant recombinant proteins are produced in E. coli for study of structure/function relationships.

Pattern of globin gene expression during human development: The fetal to adult hemoglobin "switch".

Representative Publications:

Sabatino, D.E., Cline, A.P., Gallagher, P.G., Garrett, L.J., Stamatoyannopoulos, G., Forget, B.G., Bodine, D.M. Substitution of the human b-spectrin promoter for the human Ag-globin promoter prevents silencing of a linked human b-globin gene in transgenic mice. Mol. Cell. Biol. 18:6634-6640, 1998.

Arcasoy, M.O., Harris, K.W. and Forget, B.G. A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation. Exp. Hemat. 27:63-74, 1999.

Gallagher, P.G., Sabatino, D.E., Romana, M., Cline, A.P., Garrett, L.J., Bodine, D.M., Forget, B.G. A human b-spectrin gene promoter directs high level expression in erythroid, but not muscle or neural cells. J. Biol. Chem. 274:6062-6073, 1999.

Feingold, E.A., Penny L.A., Nienhuis, A.W., Forget, B.G. An olfactory receptor gene is located in the extended human b-globin gene cluster and is expressed in erythroid cells. Genomics 61:15-23, 1999.

Dooner, G.J., Barker, J.E., Gallagher, P.G., Debatis, M.E., Brown, A.H., Forget, B.G., Becker, P.S. Gene transfer to ankyrin deficient bone marrow corrects spherocytosis in vitro. Exp. Hematol. 28:765-774, 2000.

Gallagher, P.G., Romana, M., Tse, W.T., Lux, S.E., Forget, B.G. The human ankyrin-1 gene is selectively transcribed in erythroid cell lines despite the presence of a housekeeping-like promoter. Blood 96:1136-1143, 2000.

<bernard.forget@yale.edu>

Updated 19 December 2000