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Series GSE63055 Query DataSets for GSE63055
Status Public on Dec 15, 2014
Title 7q11.23 dosage-dependent dysregulation in the human pluripotent state primes aberrant transcriptional programs in disease-relevant lineages (RNAseq)
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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 http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes.
 
Overall design 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 these by RNAseq (either polyA or ribo-zero). To isolate the contribution of GTF2I to the transcriptional dysregulation, we created stable lines expressing a short hairpin against GTF2I from a representative subset of these iPSC clones, and profiled by RNAseq 7 such lines along with their respective scramble controls. Finally, we also profiled by RNAseq mesenchymal stem cells (MSC) derived from a representative subset of the lines.
 
Contributor(s) Adamo A, Atashpaz S, Germain P, Zanella M, D'Agostino G, Albertin V, Chenoweth J, Micale L, Fusco C, Unger C, Augello B, Palumbo O, Hamilton B, Carella M, Donti E, Pruneri G, Selicorni A, Biamino E, Prontera P, McKay R, Merla G, Testa G
Citation(s) 25501393, 27190234
Submission date Nov 06, 2014
Last update date May 15, 2019
Contact name Giuseppe Testa
E-mail(s) giuseppe.testa@ieo.it
Organization name European Institute of Oncology & University of Milano, Italy
Lab Neurogenomics Research Centre
Street address Via Adamello, 16
City Milano
ZIP/Postal code 20139
Country Italy
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (57)
GSM1538995 iPSC 7dupASD2-C2 (GDB-242_J) ribo-zero RNAseq
GSM1538996 iPSC WBS3-C2 (GDB-361_O) ribo-zero RNAseq
GSM1538997 iPSC WBS4-C1 (GDB-306_O) ribo-zero RNAseq
This SubSeries is part of SuperSeries:
GSE63058 7q11.23 dosage-dependent dysregulation in the human pluripotent state primes aberrant transcriptional programs in disease-relevant lineages
Relations
BioProject PRJNA266526
SRA SRP049593

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE63055_allSamples_genes.fpkm_table.txt.gz 3.9 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record
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