A liver-specific nuclear protein represses transcription of the S14 gene in vitro and in vivo.

P1 is a nuclear protein found exclusively in rat liver and binds to a motif that spans nucleotides -310 to -288 of the thyroid hormone responsive gene, S14. We expect P1 to play an important role in regulating gene expression because the binding motif for this factor is contained within a DNase I-hypersensitive site of S14 chromatin. In this report, we have attempted to define the function of P1 by correlating its DNA binding activity with levels of mRNA-S14 in response to aging and obesity. Results of all studies revealed inverse relationships between the activity of P1 and levels of mRNA-S14, thus suggesting that P1 may function as a repressor of S14 gene expression. Accordingly, we tested the repressor hypothesis using cell-free transcription and transient transfection assays to measure the activity of reporter constructs with and without the P1 binding motif. In the presence of the P1 motif, S14 promoter activity was repressed and the negative effect on gene transcription was further enhanced by thyroid hormone. These observations are consistent with P1 being a repressor of S14 gene transcription.