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

Nat Genet. 2015 Feb;47(2):132-41. doi: 10.1038/ng.3169. Epub 2014 Dec 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Lineage
  • Chromosomes, Human, Pair 7 / genetics*
  • Cohort Studies
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations*
  • Gene Dosage
  • Gene Duplication
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics*
  • Histone Demethylases / genetics
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Pluripotent Stem Cells / pathology
  • Pluripotent Stem Cells / physiology*
  • Sequence Analysis, RNA
  • Transcription Factors, TFII / genetics*
  • Williams Syndrome / genetics*


  • GTF2I protein, human
  • Transcription Factors, TFII
  • Histone Demethylases
  • KDM1A protein, human

Associated data

  • GEO/GSE63058