The transcription factors HNF3 (FoxA) and GATA-4 are the earliest known to bind the albumin gene enhancer in liver precursor cells in embryos. To understand how they access sites in silent chromatin, we assembled nucleosome arrays containing albumin enhancer sequences and compacted them with linker histone. HNF3 and GATA-4, but not NF-1, C/EBP, and GAL4-AH, bound their sites in compacted chromatin and opened the local nucleosomal domain in the absence of ATP-dependent enzymes. The ability of HNF3 to open chromatin is mediated by a high affinity DNA binding site and by the C-terminal domain of the protein, which binds histones H3 and H4. Thus, factors that potentiate transcription in development are inherently capable of initiating chromatin opening events.
The Forkhead 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, FoxE1 binds to the compacted chromatin of the inactive thyroperoxidase (TPO) promoter, which coincides with the appearance of strong DNase I hypersensitivity at the FoxE1 binding site. In vitro, FoxE1 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 1 binds to the TPO promoter simultaneously with FoxE1, and this binding has an additive effect on FoxE1-mediated chromatin structure alteration. On the basis of our findings, we propose that FoxE1 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.
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