title: Huntingtin facilitates polycomb repressive complex 2.
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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Woda
authors.forename: Ji-Joon
authors.initials: JJ
authors.lastname: Song
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lloret
authors.forename: Priyanka D
authors.initials: PD
authors.lastname: Abeyrathne
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Woo
authors.forename: Gillian
authors.initials: G
authors.lastname: Gregory
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Robert E
authors.initials: RE
authors.lastname: Kingston
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Conlon
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: C086055:HTT protein, human; D006657:Histones; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins