title: Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice.
abstract: Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kraft
authors.forename: Ion Cristian
authors.initials: IC
authors.lastname: Cirstea
authors.forename: Anne Kathrin
authors.initials: AK
authors.lastname: Voss
authors.forename: Tim
authors.initials: T
authors.lastname: Thomas
authors.forename: Ina
authors.initials: I
authors.lastname: Goehring
authors.forename: Bilal N
authors.initials: BN
authors.lastname: Sheikh
authors.forename: Lavinia
authors.initials: L
authors.lastname: Gordon
authors.forename: Hamish
authors.initials: H
authors.lastname: Scott
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Udo
authors.initials: U
authors.lastname: Trautmann
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Arif
authors.initials: A
authors.lastname: Ekici
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Helmuth-Guenther
authors.initials: HG
authors.lastname: Dörr
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Christian Thomas
authors.initials: CT
authors.lastname: Thiel
mesh_terms: D000818:Animals; D002648:Child; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human; C496555:Kat6b protein, mouse; D020928:Mitogen-Activated Protein Kinases