Huntingtin facilitates polycomb repressive complex 2

• Published in: Human molecular genetics Vol. 19; no. 4; pp. 573 - 583
• Main Authors: Seong, Ihn Sik, Woda, Juliana M., Song, Ji-Joon, Lloret, Alejandro, Abeyrathne, Priyanka D., Woo, Caroline J., Gregory, Gillian, Lee, Jong-Min, Wheeler, Vanessa C., Walz, Thomas, Kingston, Robert E., Gusella, James F., Conlon, Ronald A., MacDonald, Marcy E.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.02.2010
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Histones - genetics; Histones - metabolism; Humans; Huntingtin Protein; Huntington Disease - embryology; Huntington Disease - genetics; Huntington Disease - metabolism; Male; Mice; Mice, Knockout; Molecular and cellular biology; Molecular Sequence Data; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Polycomb-Group Proteins; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; Sequence Homology, Amino Acid; Huntingtin; Genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp524

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 HdhQ111 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.