Regulation of Gene Expression

Reitman, M.

Abstract

Our goal is to understand two aspects of gene regulation: 1) the mechanisms that operate to 'open' chromatin and 2) those that dictate how a particular gene within an open multi-gene cluster is chosen for expression. The model evolving from studies of the human beta-globin cluster is that control elements upstream of the genes provide a locus activation function. These upstream elements also increase the expression of the nearest available genes, with availability determined by the promoter. Human diseases with defects in each of these processes are known (eg. beta-thalassemia (Hispanic form) and hereditary persistence of fetal hemoglobin). Knowledge of these topics is part of the background needed for a rational approach to gene therapy. We previously demonstrated that the chicken beta(A)-globin gene and its 3' enhancer contain information sufficient to guarantee copy-number dependent expression in transgenic mice, independent of the site of transgene integration (this property defines a locus control region, LCR). To study the way in which an enhancer/locus control region activates chromatin, we examined transgenic mice carrying various combinations of the chicken beta(A)-globin gene coding region, promoter and 3' enhancer/LCR. The results support a 'mutual interaction' model for the mechanism of chromatin opening by LCRs in which an enhancer/LCR and a promoter must cooperate to generate open chromatin.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Type: Intramural Research (Z01)
• Project #: 1Z01DK047031-02
• Application #: 3776865
• Support Year: 2
• Fiscal Year: 1993

Institution

• Name: National Institute of Diabetes and Digestive and Kidney Diseases
• Country: United States

Publications

Yamauchi, T; Kamon, J; Waki, H et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941-6

Ebihara, K; Ogawa, Y; Masuzaki, H et al. (2001) Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50:1440-8

Reitman, M L; Bi, S; Marcus-Samuels, B et al. (2001) Leptin and its role in pregnancy and fetal development--an overview. Biochem Soc Trans 29:68-72

Tansey, J T; Sztalryd, C; Gruia-Gray, J et al. (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci U S A 98:6494-9

Gavrilova, O; Marcus-Samuels, B; Graham, D et al. (2000) Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 105:271-8

Reitman, M L; Arioglu, E; Gavrilova, O et al. (2000) Lipoatrophy revisited. Trends Endocrinol Metab 11:410-6

Arioglu, E; Duncan-Morin, J; Sebring, N et al. (2000) Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 133:263-74

Kim, J K; Gavrilova, O; Chen, Y et al. (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275:8456-60

Gavrilova, O; Marcus-Samuels, B; Reitman, M L (2000) Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice. Diabetes 49:1910-6

Yu, S; Gavrilova, O; Chen, H et al. (2000) Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J Clin Invest 105:615-23