An array of positioned nucleosomes potentiates thyroid hormone receptor action in vivo.
The assembly of the genome into chromatin imposes a poorly understood set of rules and constraints on action by regulatory factors. We investigated the role played by chromatin infrastructure in enabling an acute response of the Xenopus TRbetaA gene to thyroid hormone receptor (TR), an extensively studied member of the nuclear hormone receptor superfamily. We found that in addition to the known TR response element (TRE) in the promoter, full range regulation required an upstream enhancer that contained multiple nonconsensus TREs and augmented ligand action at high receptor levels. An array of translationally positioned nucleosomes formed over the TRbetaA locus in vivo; unliganded TR engaged this array in linker DNA between two nucleosomes and via TREs on the surface of histone octamers. Remarkably, assembly of enhancer DNA into mature chromatin potentiated binding by TR to its target response elements and enabled a greater range of regulation by TR than was observed on immature chromatin templates. Because assembly of enhancer DNA into chromatin increased TR binding to the nonconsensus TREs, we hypothesize that chromatin disruption targeted by liganded TR to the enhancer may lead to receptor release from the template and to an attenuation of response to hormone.
Urnov
F D
FD
Sangamo Biosciences, Point Richmond Tech Center, Richmond, California 94804, USA. furnov@sangamo.com
Wolffe
A P
AP
D000818:Animals; D001483:Base Sequence; D004247:DNA; D004742:Enhancer Elements, Genetic; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014284:Triiodothyronine / Q000502:physiology; D014981:Xenopus
D009707:Nucleosomes; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D004247:DNA