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EcR recruits dMi-2 and increases efficiency of dMi-2-mediated remodelling to constrain transcription of hormone-regulated genes

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ABSTRACT

Gene regulation by steroid hormones plays important roles in health and disease. In Drosophila, the hormone ecdysone governs transitions between key developmental stages. Ecdysone-regulated genes are bound by a heterodimer of ecdysone receptor (EcR) and Ultraspiracle. According to the bimodal switch model, steroid hormone receptors recruit corepressors in the absence of hormone and coactivators in its presence. Here we show that the nucleosome remodeller dMi-2 is recruited to ecdysone-regulated genes to limit transcription. Contrary to the prevalent model, recruitment of the dMi-2 corepressor increases upon hormone addition to constrain gene activation through chromatin remodelling. Furthermore, EcR and dMi-2 form a complex that is devoid of Ultraspiracle. Unexpectedly, EcR contacts the dMi-2 ATPase domain and increases the efficiency of dMi-2-mediated nucleosome remodelling. This study identifies a non-canonical EcR-corepressor complex with the potential for a direct regulation of ATP-dependent nucleosome remodelling by a nuclear hormone receptor.

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Model.Model detailing hormone-dependent (bimodal switch model) and hormone-independent modes of gene regulation by EcR. EcR can heterodimerize with either dMi-2 or USP. EcR–USP heterodimers recruit corepressor (CoR) or coactivator (CoA) complexes in a hormone-dependent manner. dMi-2 recruitment is independent of hormone. dMi-2 binds to EcR monomers or homodimers in solution (left) or DNA-bound EcR monomers/homodimers that are generated by monomer/homodimer binding to DNA (middle) or by dissociation of DNA-bound EcR–USP heterodimer (right). EcR activates dMi-2 nucleosome remodelling activity.
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f7: Model.Model detailing hormone-dependent (bimodal switch model) and hormone-independent modes of gene regulation by EcR. EcR can heterodimerize with either dMi-2 or USP. EcR–USP heterodimers recruit corepressor (CoR) or coactivator (CoA) complexes in a hormone-dependent manner. dMi-2 recruitment is independent of hormone. dMi-2 binds to EcR monomers or homodimers in solution (left) or DNA-bound EcR monomers/homodimers that are generated by monomer/homodimer binding to DNA (middle) or by dissociation of DNA-bound EcR–USP heterodimer (right). EcR activates dMi-2 nucleosome remodelling activity.

Mentions: Our results extend the bimodal switch model for EcR function (Fig. 7). The EcR–USP heterodimer provides hormone-dependent regulation of transcription as postulated by the bimodal switch model. In addition, the alternative EcR-dMi-2 complex constrains transcription in a hormone-independent manner. We propose that EcR-dMi-2 complexes form in the nucleoplasm and then bind to DNA or that EcR binds to DNA as a monomer/dimer followed by dMi-2 recruitment. Also, dissociation of EcR–USP heterodimers on chromatin provides additional EcR monomers capable of recruiting Mi-2. In the presence of hormone, more EcR and USP enter the nucleus and the amount of DNA-bound EcR–USP increases6. This in turn would be expected to increase the number of DNA-bound EcR monomers resulting in increased dMi-2 chromatin association and thus would prevent an excessive transcriptional response.


EcR recruits dMi-2 and increases efficiency of dMi-2-mediated remodelling to constrain transcription of hormone-regulated genes
Model.Model detailing hormone-dependent (bimodal switch model) and hormone-independent modes of gene regulation by EcR. EcR can heterodimerize with either dMi-2 or USP. EcR–USP heterodimers recruit corepressor (CoR) or coactivator (CoA) complexes in a hormone-dependent manner. dMi-2 recruitment is independent of hormone. dMi-2 binds to EcR monomers or homodimers in solution (left) or DNA-bound EcR monomers/homodimers that are generated by monomer/homodimer binding to DNA (middle) or by dissociation of DNA-bound EcR–USP heterodimer (right). EcR activates dMi-2 nucleosome remodelling activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382322&req=5

f7: Model.Model detailing hormone-dependent (bimodal switch model) and hormone-independent modes of gene regulation by EcR. EcR can heterodimerize with either dMi-2 or USP. EcR–USP heterodimers recruit corepressor (CoR) or coactivator (CoA) complexes in a hormone-dependent manner. dMi-2 recruitment is independent of hormone. dMi-2 binds to EcR monomers or homodimers in solution (left) or DNA-bound EcR monomers/homodimers that are generated by monomer/homodimer binding to DNA (middle) or by dissociation of DNA-bound EcR–USP heterodimer (right). EcR activates dMi-2 nucleosome remodelling activity.
Mentions: Our results extend the bimodal switch model for EcR function (Fig. 7). The EcR–USP heterodimer provides hormone-dependent regulation of transcription as postulated by the bimodal switch model. In addition, the alternative EcR-dMi-2 complex constrains transcription in a hormone-independent manner. We propose that EcR-dMi-2 complexes form in the nucleoplasm and then bind to DNA or that EcR binds to DNA as a monomer/dimer followed by dMi-2 recruitment. Also, dissociation of EcR–USP heterodimers on chromatin provides additional EcR monomers capable of recruiting Mi-2. In the presence of hormone, more EcR and USP enter the nucleus and the amount of DNA-bound EcR–USP increases6. This in turn would be expected to increase the number of DNA-bound EcR monomers resulting in increased dMi-2 chromatin association and thus would prevent an excessive transcriptional response.

View Article: PubMed Central - PubMed

ABSTRACT

Gene regulation by steroid hormones plays important roles in health and disease. In Drosophila, the hormone ecdysone governs transitions between key developmental stages. Ecdysone-regulated genes are bound by a heterodimer of ecdysone receptor (EcR) and Ultraspiracle. According to the bimodal switch model, steroid hormone receptors recruit corepressors in the absence of hormone and coactivators in its presence. Here we show that the nucleosome remodeller dMi-2 is recruited to ecdysone-regulated genes to limit transcription. Contrary to the prevalent model, recruitment of the dMi-2 corepressor increases upon hormone addition to constrain gene activation through chromatin remodelling. Furthermore, EcR and dMi-2 form a complex that is devoid of Ultraspiracle. Unexpectedly, EcR contacts the dMi-2 ATPase domain and increases the efficiency of dMi-2-mediated nucleosome remodelling. This study identifies a non-canonical EcR-corepressor complex with the potential for a direct regulation of ATP-dependent nucleosome remodelling by a nuclear hormone receptor.

No MeSH data available.


Related in: MedlinePlus