Huntingtin facilitates polycomb repressive complex 2
| Autor: | Priyanka D. Abeyrathne, Ji-Joon Song, Marcy E. MacDonald, Caroline J. Woo, Thomas Walz, Ihn Sik Seong, Ronald A. Conlon, Robert E. Kingston, Gillian C. Gregory, Vanessa C. Wheeler, Alejandro Lloret, Jong-Min Lee, James F. Gusella, Juliana M. Woda |
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| Rok vydání: | 2009 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Huntingtin Molecular Sequence Data Polycomb-Group Proteins Nerve Tissue Proteins macromolecular substances Biology Histones Mice 03 medical and health sciences 0302 clinical medicine SETD2 mental disorders Genetics Polycomb-group proteins Huntingtin Protein Animals Humans Molecular Biology Genetics (clinical) 030304 developmental biology Mice Knockout 0303 health sciences Sequence Homology Amino Acid Nuclear Proteins Articles General Medicine Trophoblast giant cell differentiation Chromatin Repressor Proteins Disease Models Animal Huntington Disease Histone biology.protein Female PRC2 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddp524 |
| Popis: | 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 alpha-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 alpha-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 alpha-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. |
| Databáze: | OpenAIRE |
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