Allosteric Effects of Pit-1 DNA Sites on Long-Term Repression in Cell Type Specification

• Published in: Science (American Association for the Advancement of Science) Vol. 290; no. 5494; pp. 1127 - 1131
• Main Authors: Scully, Kathleen M., Jacobson, Eric M., Jepsen, Kristen, Lunyak, Victoria, Viadiu, Hector, Carrière, Catherine, Rose, David W., Hooshmand, Farideh, Aggarwal, Aneel K., Rosenfeld, Michael G.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 10.11.2000; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Allosteric Regulation; Animals; Antibodies; B lymphocytes; Base Sequence; Binding Sites; Biological and medical sciences; Cell differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cells; Conserved Sequence; Crystallization; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genes; Genes, Reporter; Growth Hormone - genetics; Growth hormones; Growth promotion; Hormone research; Individualized Instruction; lactotrope; Male; Methods; Mice; Mice, Transgenic; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Monomers; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Receptor Co-Repressor 1; Pit-1 gene; Pituitary gland; Pituitary Gland - cytology; Pituitary Gland - metabolism; Prolactin - genetics; Promoter Regions, Genetic; Protein Conformation; Protein Structure, Tertiary; Rats; Repression; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Article; somatotrope; Transcription Factor Pit-1; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Transgenic animals; United States; Vertebrata; Regulation(control); Mammalia; Targeting; Gene; DNA; Somatotropin hormone; Molecular complex; Prolactin cell; Somatotropic cell; Cell differentiation; Gene expression
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.290.5494.1127

Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question, then, is whether a critical transcriptional activator of cell type-specific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitary-specific POU domain factor Pit-1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lactotrope. This distinction depends on a two-base pair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on Pit-1, in combination with other DNA binding factors, results in the recruitment of a corepressor complex, including nuclear receptor corepressor N-CoR, which, unexpectedly, is required for active long-term repression of the growth hormone gene in lactotropes.