title: 7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages.
abstract: Cell reprogramming promises to make characterization of the impact of human genetic variation on health and disease experimentally tractable by enabling the bridging of genotypes to phenotypes in developmentally relevant human cell lineages. Here we apply this paradigm to two disorders caused by symmetrical copy number variations of 7q11.23, which display a striking combination of shared and symmetrically opposite phenotypes--Williams-Beuren syndrome and 7q-microduplication syndrome. Through analysis of transgene-free patient-derived induced pluripotent stem cells and their differentiated derivatives, we find that 7q11.23 dosage imbalance disrupts transcriptional circuits in disease-relevant pathways beginning in the pluripotent state. These alterations are then selectively amplified upon differentiation of the pluripotent cells into disease-relevant lineages. A considerable proportion of this transcriptional dysregulation is specifically caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Adamo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Sina
authors.identifier: 0000000305665629
authors.initials: S
authors.lastname: Atashpaz
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Pierre-Luc
authors.identifier: 0000000334184218
authors.initials: PL
authors.lastname: Germain
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanella
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Albertin
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Chenoweth
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Micale
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Fusco
authors.affiliation: Department of Biomedical Sciences, University of Sheffield, Sheffield, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Unger
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Augello
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Stemgent, Cambridge, Massachusetts, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Hamilton
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Medical Genetics Unit, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Donti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Unità Operativa Semplice (UOS) Genetica Clinica Pediatrica, Fondazione Monza e Brianza per il Bambino e la sua Mamma (Fondazione MBBM), Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Department of Pediatrics, University of Turin, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Biamino
authors.affiliation: Medical Genetics Unit, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Prontera
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: McKay
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
authors.forename: Giuseppe
authors.identifier: 000000015078928X
authors.initials: G
authors.lastname: Merla
authors.affiliation: 1] Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy. [2] Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.identifier: 0000000291040918
authors.initials: G
authors.lastname: Testa
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D020440:Gene Duplication; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D056466:Histone Demethylases / Q000235:genetics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000473:pathology / Q000502:physiology*; D017423:Sequence Analysis, RNA; D019473:Transcription Factors, TFII / Q000235:genetics*; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: C104259:GTF2I protein, human; D019473:Transcription Factors, TFII; D056466:Histone Demethylases; C495195:KDM1A protein, human