ABSTRACT
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.
Subject(s)
DNA-Binding Proteins/metabolism , DNA/metabolism , Gene Expression Regulation , Growth Hormone/genetics , Pituitary Gland/metabolism , Prolactin/genetics , Repressor Proteins/metabolism , Transcription Factors/metabolism , Allosteric Regulation , Animals , Base Sequence , Binding Sites , Cell Line , Conserved Sequence , Crystallization , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Female , Genes, Reporter , Male , Mice , Mice, Transgenic , Models, Molecular , Molecular Sequence Data , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nuclear Receptor Co-Repressor 1 , Pituitary Gland/cytology , Promoter Regions, Genetic , Protein Conformation , Protein Structure, Tertiary , Rats , Repressor Proteins/chemistry , Repressor Proteins/genetics , Transcription Factor Pit-1 , Transcription Factors/chemistry , Transcription Factors/genetics , Transcriptional ActivationABSTRACT
Transcriptional repression plays crucial roles in diverse aspects of metazoan development, implying critical regulatory roles for corepressors such as N-CoR and SMRT. Altered patterns of transcription in tissues and cells derived from N-CoR gene-deleted mice and the resulting block at specific points in CNS, erythrocyte, and thymocyte development indicated that N-CoR was a required component of short-term active repression by nuclear receptors and MAD and of a subset of long-term repression events mediated by REST/NRSF. Unexpectedly, N-CoR and a specific deacetylase were also required for transcriptional activation of one class of retinoic acid response element. Together, these findings suggest that specific combinations of corepressors and histone deacetylases mediate the gene-specific actions of DNA-bound repressors in development of multiple organ systems.
