A zinc finger homeodomain transcription factor binds specific thyroid hormone response elements.

Thyroid hormone receptors can act through response elements (TREs) having a wide variation of sequence. We screened for transcription factors that bind the rat (r) glycoprotein hormone alpha-subunit TRE (alpha-sub), and isolated a cDNA, termed zinc finger homeodomain enhancer-binding protein (Zfhep), which encodes two separate zinc finger domains (ZD1 and ZD2), and a region similar to homeodomains. DNA-binding assays show that ZD1 or ZD2 can bind the alpha-subunit, rat growth hormone, or thyrotropin beta (TSHbeta) gene TREs, but do not bind DR4 or palindromic (pal) TREs. Methylation interference footprinting demonstrates that Zfhep binds the alpha-sub overlapping the TR-binding site. Similarly, the ZD1 protein footprints over TR-binding halfsites of the rat growth hormone (rGH) and TSHbeta TREs. Hence, Zfhep binding is dependent on sequences within and outside the AGGTCA TR-binding halfsite. Interactions of non-receptor transcription factors (such as Zfhep) with certain TREs are important to modify gene-specific regulation by thyroid hormones.