Huntingtin Facilitates Polycomb Repressive Complex 2
| Title: | Huntingtin Facilitates Polycomb Repressive Complex 2 |
| Author: |
Woda, Juliana M.; Song, Ji-Joon; Lloret, Alejandro; Abeyrathne, Priyanka D.; Gregory, Gillian; Lee, Jong-Min; Conlon, Ronald A.; Seong, Ihn Sik; Woo, Caroline; Wheeler, Vanessa Chantal; Walz, Thomas; Kingston, Robert Edward; Gusella, James Francis; MacDonald, Marcy Elizabeth
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | Seong, Ihn Sik, Juliana M. Woda, Ji-Joon Song, Alejandro Lloret, Priyanka D. Abeyrathne, Caroline J. Woo, Gillian Gregory, et al. 2010. Huntingtin facilitates polycomb repressive complex 2. Human Molecular Genetics 19(4): 573-583. |
| Full Text & Related Files: |
2807366.pdf (366.0Kb; PDF) 
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| Abstract: | Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat α-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating two large α-helical domains. Moreover, embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X chromosome inactivation and histone H3K27 tri-methylation, while full-length endogenous nuclear huntingtin in wild-type embryoid bodies (EBs) was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9. Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 tri-methylase activity of reconstituted PRC2 in vitro, and structure–function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in \(Hdh^{Q111}\) EBs and in vitro, with reconstituted PRC2. Knowledge of full-length huntingtin's α-helical organization and role as a facilitator of the multi-subunit PRC2 complex provides a novel starting point for studying PRC2 regulation, implicates this chromatin repressive complex in a neurodegenerative disorder and sets the stage for further study of huntingtin's molecular function and the impact of its modulatory polyglutamine region. |
| Published Version: | doi:10.1093/hmg/ddp524 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807366/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:5346712 |
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