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Huntingtin facilitates polycomb repressive complex 2.

Human molecular genetics | Feb 15, 2010

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.

Pubmed ID: 19933700 RIS Download

Mesh terms: Animals | Disease Models, Animal | Female | Histones | Humans | Huntingtin Protein | Huntington Disease | Male | Mice | Mice, Knockout | Molecular Sequence Data | Nerve Tissue Proteins | Nuclear Proteins | Polycomb-Group Proteins | Protein Binding | Repressor Proteins | Sequence Homology, Amino Acid

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Associated grants

  • Agency: NIGMS NIH HHS, Id: P01 GM062580
  • Agency: NINDS NIH HHS, Id: R01 NS049206
  • Agency: NIGMS NIH HHS, Id: GM62580

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Web application for sequence analysis and the prediction of protein structure and function. The user interface intakes protein sequences or alignments and returned multiple sequence alignments, motifs, and nuclear localization signals.

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Tool to align three or more sequences together in a computationally efficient manner. This multiple sequence alignment program for DNA or proteins attempts to calculate the best match for the selected sequences, and lines them up so that the identities, similarities and differences can be seen. Evolutionary relationships can be seen via viewing Cladograms or Phylograms. The alignment is progressive and considers sequence redundancy. SOAP Web services are also available. Note: ClustalW2 is no longer being maintained. Please consider using the new version instead: Clustal Omega, http://www.ebi.ac.uk/Tools/msa/clustalo/ There are two ways to use this service at the EBI. The first is interactively (default) and the second is by email. Using it interactively, the user must wait for the results to be displayed in the browser window. The email option means that the results will not be displayed in the browser window but will be sent by email. The email option is the better one to take when submitting large amounts of data. The program accepts nucleic acid or protein sequences, in the following multiple sequence formats: NBRF/PIR, EMBL/UniProt, Pearson (FASTA), GDE, ALN/ClustalW, GCG/MSF, RSF. Note: ClustalW2 is no longer being maintained. Please consider using the new version instead: Clustal Omega

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