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

Antonio Adamo, Sina Atashpaz, Pierre Luc Germain, Matteo Zanella, Giuseppe D'Agostino, Veronica Albertin, Josh Chenoweth, Lucia Micale, Carmela Fusco, Christian Unger, Bartolomeo Augello, Orazio Palumbo, Brad Hamilton, Massimo Carella, Emilio Donti, Giancarlo Pruneri, Angelo Selicorni, Elisa Biamino, Paolo Prontera, Ronald McKayGiuseppe Merla, Giuseppe Testa

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)132-141
Number of pages10
JournalNature Genetics
Volume47
Issue number2
DOIs
Publication statusPublished - Jan 1 2015

ASJC Scopus subject areas

  • Genetics

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