MOZ Regulates the Tbx1 Locus, and Moz Mutation Partially Phenocopies DiGeorge Syndrome

• Published in: Developmental cell Vol. 23; no. 3; pp. 652 - 663
• Main Authors: Voss, Anne K., Vanyai, Hannah K., Collin, Caitlin, Dixon, Mathew P., McLennan, Tamara J., Sheikh, Bilal N., Scambler, Peter, Thomas, Tim
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 11.09.2012; Cell Press
• Subjects: Animals; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; DiGeorge Syndrome - genetics; DiGeorge Syndrome - metabolism; Fundamental and applied biological sciences. Psychology; Histone Acetyltransferases - deficiency; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Mice; Mice, Inbred Strains; Mice, Transgenic; Molecular and cellular biology; Mutation; Phenotype; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Immunopathology; Phenocopy; Regulation(control); Development; Di George's syndrome; Mutation; Locus
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2012.07.010

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. ► Homozygous mutation of Moz causes DiGeorge syndrome-like anomalies ► MOZ is required for palate, thymus, aortic arch, and cardiac septal development ► MOZ acts through H3K9 acetylation and promotion of transcription at the Tbx1 locus ► Mutation of Moz sensitizes embryonic development to environmental insults Voss et al. show that loss of the histone acetyltransferase Moz disrupts histone H3K9 acetylation and transcription of Tbx1. A Tbx1 transgene partially rescues DiGeorge syndrome-like phenotypes in Moz mutant mice. Moz mutants offer opportunities to study how environmental insults such as retinoids influence genetic models of disease.