Methylation patterns of human parathyroid hormone (PTH)/PTH-related peptide receptor gene promoters are established several weeks prior to onset of their function

Expression of the human parathyroid hormone (PTH)/ PTH-related peptide rece ptor (PTHR) gene is controlled by three promoters, P1-P3, P1 functions spec ifically in kidney, whereas P2 is ubiquitously active. P3 is also widely ac tive, although more so in kidney than other tissues. However, only P2 funct ions at midgestation. We examined the role of methylation in controlling PT HR promoter activity. Function of all promoters was inhibited by CpG methyl ation in vitro. Significantly, P1 is selectively hypomethylated in adult ki dney in vivo strongly suggesting that demethylation is required for renal P 1 function. Moreover, this pattern is established by 11.75 weeks of fetal a ge, several weeks prior to the onset P1 activity. P3 is unmethylated at mid gestation, although it is inactive at this stage of development, and thus e xhibits characteristics of both tissue-specific and ubiquitously active pro moters. These results show that adult methylation patterns of P1 and P3 are established several weeks prior to their induction, indicating that their function requires factors expressed late in development. (C) 2000 Academic Press.