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Nat Genet. 2015 Feb;47(2):132-41. doi: 10.1038/ng.3169. Epub 2014 Dec 15.

7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages.

Author information

1
Department of Experimental Oncology, European Institute of Oncology (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS), Milan, Italy.
2
Lieber Institute for Brain Development, Baltimore, Maryland, USA.
3
Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.
4
Department of Biomedical Sciences, University of Sheffield, Sheffield, UK.
5
Stemgent, Cambridge, Massachusetts, USA.
6
Medical Genetics Unit, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy.
7
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.
8
Department of Pediatrics, University of Turin, Turin, Italy.
9
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.

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.

PMID:
25501393
DOI:
10.1038/ng.3169
[Indexed for MEDLINE]

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