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7q11.23 dosage-dependent dysregulation in the human pluripotent state primes aberrant transcriptional programs in disease-relevant lineages (aCGH)

ABSTRACT: We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dupASD). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes. We reprogrammed skin fibroblasts from patients harbouring a 7q11.23 hemi-deletion (WBS, 4 patients; +1 atypical deletion, AtWBS) or microduplication (7dupASD; 2 patients), as well as from one unaffected relative and two unrelated controls, using integration-free mRNA-reprogramming, leading to the establishment of a total of 27 characterized iPSC clones. We profiled by aCGH each established iPSC clone as well as the original fibroblasts (for all patients and the unaffected relative).

ORGANISM(S): Homo sapiens  

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

PROVIDER: E-GEOD-63028 | ArrayExpress | 2015-01-02



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