Regulation of the human growth hormone gene family: possible role for Pit-1 in early stages of pituitary-specific expression and repression

Abstract

The somatic cells of a multicellular organism contain an identical complement of genes that need to be expressed specifically and appropriately to allow the normal development and functions associated with an organism. In the eukaryotic cell nucleus, genes are packaged with nucleoprotein histones into chromatin. The human growth hormone (GH)/chorionic somatomammotropin (CS) gene family offers an excellent model to study the relationship between chromatin structure and transcription factor binding in terms of tissue-specific gene expression. The GH/CS gene family consists of five genes (GH-N, GH-V, CS-A, CS-B and CS-L), contained in a single locus on chromosome 17. Although they share approximately 94% sequence similarity, GH-N expression is restricted to pituitary somatotropes while the four placental GH/CS genes are expressed in the villus syncytiotrophoblast. Appropriate expression in vivo is dependent on remote sequences found 14-32 kb upstream of GH-N in the loci of adjacent genes, and these sequences are characterized by five (I-V) nuclease-hypersensitive sites (HS). Pituitary-specific factor Pit-1 binds at HS I/II and plays an essential role in chromatin remodeling and GH-N expression; however, the processes that lead to HS I/II accessibility are unknown. We discuss the possibility that Pit-1-driven remodeling at HS III may precede that at HS I/II in the pituitary. Also, in pituitary chromatin, all five GH/CS genes share similar nuclease sensitivity, suggesting that the conformation of the placental genes is not inhibitory to transcription. Given that the promoters of both GH-N and the placental GH/CS genes contain Pit-1-binding sites, possible mechanisms to restrict placenta GH/CS promoter activity in the pituitary are discussed, including active repression via P sequences located upstream of each of the placental GH/CS genes. Positively or negatively influencing those components known to be important for pituitary transcription may link epigenetic events to key transcription factors in the overall picture of tissue-specific control of gene expression.