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.

7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages / A. Adamo, S. Atashpaz, P. Germain, M. Zanella, G. D'Agostino, V. Albertin, J. Chenoweth, L. Micale, C. Fusco, C. Unger, B. Augello, O. Palumbo, B. Hamilton, M. Carella, E. Donti, G. Pruneri, A. Selicorni, E. Biamino, P. Prontera, R. Mckay, G. Merla, G. Testa. - In: NATURE GENETICS. - ISSN 1061-4036. - 47:2(2015 Feb), pp. 132-141. [10.1038/ng.3169]

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

A. Adamo
Primo
;
P. Germain;M. Zanella;G. D'Agostino;G. Pruneri;G. Testa
Ultimo
2015

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.
Williams-Beuren-syndrome; directed differentiation; syndrome region; craniofacial development; mental-retardation; demethylase JMJD3; human brain; abnormalities; duplication; autism
Settore BIO/11 - Biologia Molecolare
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
Settore BIO/13 - Biologia Applicata
Settore MED/04 - Patologia Generale
Settore BIO/10 - Biochimica
15-dic-2014
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/283315
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