title: Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation.
abstract: The CAG repeat expansion in the Huntington's disease gene HTT extends a polyglutamine tract in mutant huntingtin that enhances its ability to facilitate polycomb repressive complex 2 (PRC2). To gain insight into this dominant gain of function, we mapped histone modifications genome-wide across an isogenic panel of mouse embryonic stem cell (ESC) and neuronal progenitor cell (NPC) lines, comparing the effects of Htt null and different size Htt CAG mutations. We found that Htt is required in ESC for the proper deposition of histone H3K27me3 at a subset of 'bivalent' loci but in NPC it is needed at 'bivalent' loci for both the proper maintenance and the appropriate removal of this mark. In contrast, Htt CAG size, though changing histone H3K27me3, is prominently associated with altered histone H3K4me3 at 'active' loci. The sets of ESC and NPC genes with altered histone marks delineated by the lack of huntingtin or the presence of mutant huntingtin, though distinct, are enriched in similar pathways with apoptosis specifically highlighted for the CAG mutation. Thus, the manner by which huntingtin function facilitates PRC2 may afford mutant huntingtin with multiple opportunities to impinge upon the broader machinery that orchestrates developmentally appropriate chromatin status.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Department of Neurology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Biagioli
authors.affiliation: Center for Biomedical Informatics, Boston, MA 02114, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: University of Alabama in Huntsville, Huntsville, AL 35805, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Mendenhall
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Department of Neurology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vijayvargia
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Vallabh
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Solomos
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Poornima
authors.initials: P
authors.lastname: Manavalan
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Ragavendran
authors.affiliation: RaNA Therapeutics, 790 Memorial Drive, Cambridge, MA 02139, USA.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozsolak
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Department of Neurology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Department of Neurology, Harvard Medical School, Boston, MA 02114, USA, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: Macdonald
authors.affiliation: Center for Biomedical Informatics, Boston, MA 02114, USA Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA, Department of Neurology, Harvard Medical School, Boston, MA 02114, USA, iseong@mgh.harvard.edu.
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
mesh_terms: D000483:Alleles; D000818:Animals; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
chemical_list: D002843:Chromatin; D006657:Histones; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2