A novel system for correcting large-scale chromosomal aberrations: ring chromosome correction via reprogramming into induced pluripotent stem cell (iPSC)

Abstract

Approximately 1 in 500 newborns are born with chromosomal abnormalities that include trisomies, translocations, large deletions, and duplications. There is currently no therapeutic approach for correcting such chromosomal aberrations in vivo or in vitro. When we attempted to produce induced pluripotent stem cell (iPSC) models from patient-derived fibroblasts that contained ring chromosomes, we found that the ring chromosomes were eliminated and replaced by duplicated normal copies of chromosomes through a mechanism of uniparental isodisomy (Bershteyn et al. 2014, Nature 507:99). The discovery of this previously unforeseen system for aberrant chromosome correction during reprogramming enables us for the first time to model and understand this process of cell-autonomous correction of ring chromosomes during human patient somatic cell reprograming to iPSCs. This knowledge could lead to a potential therapeutic strategy to correct common large-scale chromosomal aberrations, termed “chromosome therapy”.

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Abbreviations

(iPSCs):

Induced pluripotent stem cells

(UPD):

Compensatory uniparental disomy

(MDS):

Miller Dieker Syndrome

(ZFNs):

Engineered zinc finger nucleases

(TALENs):

Transcription activator-like effector nucleases

(CRIPSR):

Clustered regularly interspaced short palindromic repeats

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Acknowledgments

We thank Justine Ngo for the helpful discussion and comments on the manuscript.

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Correspondence to Anthony Wynshaw-Boris.

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This work was supported by a grant from Ring 14 International.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Kim, T., Plona, K. & Wynshaw-Boris, A. A novel system for correcting large-scale chromosomal aberrations: ring chromosome correction via reprogramming into induced pluripotent stem cell (iPSC). Chromosoma 126, 457–463 (2017). https://doi.org/10.1007/s00412-016-0621-6

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Keywords

  • Ring chromosomes
  • Large-scale aberration
  • Induced pluripotent stem cells (iPSCs)
  • Compensatory uniparental disomy (UPD)
  • Genome editing
  • Chromosome therapy