Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification.
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.
Scully
K M
KM
Howard Hughes Medical Institute, Department of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Jacobson
E M
EM
Jepsen
K
K
Lunyak
V
V
Viadiu
H
H
Carrière
C
C
Rose
D W
DW
Hooshmand
F
F
Aggarwal
A K
AK
Rosenfeld
M G
MG
D000494:Allosteric Regulation; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D003460:Crystallization; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D013006:Growth Hormone / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism*; D011388:Prolactin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004247:DNA; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011388:Prolactin; D012097:Repressor Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C539128:Ncor1 protein, mouse; C539129:Ncor1 protein, rat; C494185:Pou1f1 protein, mouse; C494186:Pou1f1 protein, rat