The forkhead factor FoxE1 binds to the thyroperoxidase promoter during thyroid cell differentiation and modifies compacted chromatin structure

The Forkbead box (Fox) transcription factors play diverse roles in differentiation, development, hormone responsiveness, and aging. A pioneer activity of the Forkhead factors in developmental processes has been reported, but how this may apply to other contexts of Forkhead factor regulation remains unexplored. In this study, we address the pioneer activity of the thyroid-specific factor FoxE1 during thyroid differentiation. In response to hormone induction, FoxEl binds to the compacted chromatin of the inactive thyroperoxidase (TPO) promoter, which coincides with the appearance of strong DNase I hypersensitivity at the FoxEl binding site. In vitro, FoxEl can bind to its site even when this is protected by a nucleosome, and it creates a local exposed domain specifically on H1-compacted TPO promoter-containing nucleosome arrays. Furthermore, nuclear factor I binds to the TPO promoter simultaneously with FoxEl, and this binding has an additive effect on FoxE1-mediated chromatin structure alteration. On the basis of our findings, we propose that FoxEl is a pioneer factor whose primary mechanistic role in mediating the hormonal regulation of the TPO gene is to enable other regulatory factors to access the chromatin. The presented model extends the reported pioneer activity of the Forkhead factors to processes involved in hormone-induced differentiation.