title: MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome.
abstract: DiGeorge syndrome, caused by a 22q11 microdeletion or mutation of the TBX1 gene, varies in severity greatly, even among monozygotic twins. Epigenetic phenomena have been invoked to explain phenotypic differences in individuals of identical genetic composition, although specific chromatin modifications relevant to DiGeorge syndrome are elusive. Here we show that lack of the histone acetyltransferase MOZ (MYST3/KAT6A) phenocopies DiGeorge syndrome, and the MOZ complex occupies the Tbx1 locus, promoting its expression and histone 3 lysine 9 acetylation. Importantly, DiGeorge syndrome-like anomalies are present in mice with homozygous mutation of Moz and in heterozygous Moz mutants when combined with Tbx1 haploinsufficiency or oversupply of retinoic acid. Conversely, a Tbx1 transgene rescues the heart phenotype in Moz mutants. Our data reveal a molecular mechanism for a specific chromatin modification of the Tbx1 locus intersecting with an environmental determinant, modeling variability in DiGeorge syndrome.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. avoss@wehi.edu.au
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Vanyai
authors.forename: Caitlin
authors.initials: C
authors.lastname: Collin
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Dixon
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: McLennan
authors.forename: Bilal N
authors.initials: BN
authors.lastname: Sheikh
authors.forename: Peter
authors.initials: P
authors.lastname: Scambler
authors.forename: Tim
authors.initials: T
authors.lastname: Thomas
mesh_terms: D000818:Animals; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse