RESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Regulación de la Expresión Génica , Hormona del Crecimiento/genética , Hipófisis/metabolismo , Prolactina/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Regulación Alostérica , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Secuencia Conservada , Cristalización , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Femenino , Genes Reporteros , Masculino , Ratones , Ratones Transgénicos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Hipófisis/citología , Regiones Promotoras Genéticas , Conformación Proteica , Estructura Terciaria de Proteína , Ratas , Proteínas Represoras/química , Proteínas Represoras/genética , Factor de Transcripción Pit-1 , Factores de Transcripción/química , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
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.