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Huntingtin facilitates polycomb repressive complex 2.

Authors:
Seong IS, Woda JM, Song JJ, Lloret A, Abeyrathne PD, Woo CJ, Gregory G, Lee JM, Wheeler VC, Walz T, Kingston RE, Gusella JF, Conlon RA, MacDonald ME
Affiliation:
Journal:
Human molecular genetics

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 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.

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