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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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 (US)
Pages (from-to)132-141
Number of pages10
JournalNature Genetics
Issue number2
StatePublished - Jan 1 2015
Externally publishedYes

Bibliographical note

Funding Information:
We thank the AFSW (Associazione Famiglie Sindrome di Williams) and AISW (Associazione Italiana Sindrome di Williams) for agreeing to participate and making this study possible and the Genomic and Genetic Disorder Biobank, Galliera Genetic Bank and members of the Telethon Network of Genetic Biobanks (project numbers GTB12001G and GTB12001A), along with the EuroBioBank network, for providing us with specimens. We also thank scientists at the Drug Discovery Unit, Drug Development Program (DDU-DDP) of the European Institute of Oncology (IEO) for sharing with us the two LSD1 inhibitors used in this study; A. Bachi, A. Cattaneo and P. Soffiantini from the Mass Spectrometry service of the FIRC (Fondazione Italiana per la Ricerca sul Cancro) Institute of Molecular Oncology (IFOM); F. Pisati for processing of the teratomas; P. Andrews (University of Sheffield) for sharing two control iPSC lines (CTL2-C1 and CTL2-C2; reprogrammed from CRL-2429 fibroblasts); G. Mostoslavsky and the Center for Regenerative Medicine of Boston University for sharing the BU1Cr3-1 line; G. Barbagiovanni for help with FACS profiling and analysis; and L. Marelli along with all other members of the Testa laboratory for discussion. This work was funded by the European Research Council (consolidator grant number 616441-DISEASEAVATARS to G.T.), the Italian Ministry of Health (Ricerca Corrente to G.T. and G.M. and Bando Giovani Ricercatori 2008 and 2009 to G.T.), the EPIGEN Flagship Project of the Italian National Research Council (G.T.), the Jerome-Lejeune Foundation (G.T. and G.M.), the ERA-NET Neuron Program (G.T.), the Umberto Veronesi Foundation (S.A. and G.D.) and the Federation of European Biochemical Societies (FEBS; fellowship awarded to A.A. to work in the laboratory of G.T.).

Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.

ASJC Scopus subject areas

  • Genetics


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