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: Ihn Sik Seong, Juliana M Woda, Ji-Joon Song, Alejandro Lloret, Priyanka D Abeyrathne, Caroline J Woo, Gillian Gregory, Jong-Min Lee, Vanessa C Wheeler, Thomas Walz, Robert E Kingston, James F Gusella, Ronald A Conlon, Marcy E MacDonald
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 4 Pg. 573-83 (Feb 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 19933700 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• HTT protein, human
• Histones
• Htt protein, mouse
• Huntingtin Protein
• Nerve Tissue Proteins
• Nuclear Proteins
• Polycomb-Group Proteins
• Repressor Proteins

Topics

• Animals
• Disease Models, Animal
• Female
• Histones (genetics, metabolism)
• Humans
• Huntingtin Protein
• Huntington Disease (embryology, genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Molecular Sequence Data
• Nerve Tissue Proteins (chemistry, genetics, metabolism)
• Nuclear Proteins (chemistry, genetics, metabolism)
• Polycomb-Group Proteins
• Protein Binding
• Repressor Proteins (genetics, metabolism)
• Sequence Homology, Amino Acid