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

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 (7dup). 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. We differentiated a representative subset of patient-derived iPSC lines into three disease-relevant lineages: dorsal telencephalic progenitors (Neural Progenitor Cells, NPC), Neural Crest Stem Cells (NCSC) and Mesenchymal Stem Cells (MSC). We profiled NCSC and NPC through microarray (current dataset), and MSC through RNA-seq.

ORGANISM(S): Homo sapiens

SUBMITTER: Giuseppe Testa 

PROVIDER: E-GEOD-63040 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress