title: HD CAG-correlated gene expression changes support a simple dominant gain of function.
abstract: Huntington's disease is initiated by the expression of a CAG repeat-encoded polyglutamine region in full-length huntingtin, with dominant effects that vary continuously with CAG size. The mechanism could involve a simple gain of function or a more complex gain of function coupled to a loss of function (e.g. dominant negative-graded loss of function). To distinguish these alternatives, we compared genome-wide gene expression changes correlated with CAG size across an allelic series of heterozygous CAG knock-in mouse embryonic stem (ES) cell lines (Hdh(Q20/7), Hdh(Q50/7), Hdh(Q91/7), Hdh(Q111/7)), to genes differentially expressed between Hdh(ex4/5/ex4/5) huntingtin null and wild-type (Hdh(Q7/7)) parental ES cells. The set of 73 genes whose expression varied continuously with CAG length had minimal overlap with the 754-member huntingtin-null gene set but the two were not completely unconnected. Rather, the 172 CAG length-correlated pathways and 238 huntingtin-null significant pathways clustered into 13 shared categories at the network level. A closer examination of the energy metabolism and the lipid/sterol/lipoprotein metabolism categories revealed that CAG length-correlated genes and huntingtin-null-altered genes either were different members of the same pathways or were in unique, but interconnected pathways. Thus, varying the polyglutamine size in full-length huntingtin produced gene expression changes that were distinct from, but related to, the effects of lack of huntingtin. These findings support a simple gain-of-function mechanism acting through a property of the full-length huntingtin protein and point to CAG-correlative approaches to discover its effects. Moreover, for therapeutic strategies based on huntingtin suppression, our data highlight processes that may be more sensitive to the disease trigger than to decreased huntingtin levels.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Jessie C
authors.initials: JC
authors.lastname: Jacobsen
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Gregory
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Woda
authors.forename: Morgan N
authors.initials: MN
authors.lastname: Thompson
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Coser
authors.forename: Vidya
authors.initials: V
authors.lastname: Murthy
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D055106:Genome-Wide Association Study; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine