Allosteric effects of Pit-1 DNA sites on long-term repression in cell typespecification

Reciprocal gene activation and restriction during cell type differentiation from a common Lineage is a hallmark of mammalian organogenesis. A key ques tion, then, is whether a critical transcriptional activator of cell type-sp ecific gene targets can also restrict expression of the same genes in other cell types. Here, we show that whereas the pituitary-specific POU domain f actor Pit-1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from a second cell type, the lacto trope. 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 facto rs, results in the recruitment of a corepressor complex. including nuclear receptor corepressor N-CoR, which, unexpectedly, is required for active Lon g-term repression of the growth hormone gene in lactotropes.