Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells. Bershteyn, M., Hayashi, Y., Desachy, G., Hsiao, E. C, Sami, S., Tsang, K. M, Weiss, L. A, Kriegstein, A. R, Yamanaka, S., & Wynshaw-Boris, A. Nature, 507(7490):99–103, January, 2014. abstract bibtex Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of 'chromosome therapy' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.
@ARTICLE{Bershteyn2014-ih,
title = "Cell-autonomous correction of ring chromosomes in human induced
pluripotent stem cells",
author = "Bershteyn, Marina and Hayashi, Yohei and Desachy, Guillaume and
Hsiao, Edward C and Sami, Salma and Tsang, Kathryn M and Weiss,
Lauren A and Kriegstein, Arnold R and Yamanaka, Shinya and
Wynshaw-Boris, Anthony",
abstract = "Ring chromosomes are structural aberrations commonly associated
with birth defects, mental disabilities and growth retardation.
Rings form after fusion of the long and short arms of a
chromosome, and are sometimes associated with large terminal
deletions. Owing to the severity of these large aberrations that
can affect multiple contiguous genes, no possible therapeutic
strategies for ring chromosome disorders have been proposed.
During cell division, ring chromosomes can exhibit unstable
behaviour leading to continuous production of aneuploid progeny
with low viability and high cellular death rate. The overall
consequences of this chromosomal instability have been largely
unexplored in experimental model systems. Here we generated human
induced pluripotent stem cells (iPSCs) from patient fibroblasts
containing ring chromosomes with large deletions and found that
reprogrammed cells lost the abnormal chromosome and duplicated
the wild-type homologue through the compensatory uniparental
disomy (UPD) mechanism. The karyotypically normal iPSCs with
isodisomy for the corrected chromosome outgrew co-existing
aneuploid populations, enabling rapid and efficient isolation of
patient-derived iPSCs devoid of the original chromosomal
aberration. Our results suggest a fundamentally different
function for cellular reprogramming as a means of 'chromosome
therapy' to reverse combined loss-of-function across many genes
in cells with large-scale aberrations involving ring structures.
In addition, our work provides an experimentally tractable human
cellular system for studying mechanisms of chromosomal number
control, which is of critical relevance to human development and
disease.",
journal = "Nature",
volume = 507,
number = 7490,
pages = "99--103",
month = jan,
year = 2014,
language = "en"
}
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R","Yamanaka, S.","Wynshaw-Boris, A."],"bibdata":{"bibtype":"article","type":"article","title":"Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells","author":[{"propositions":[],"lastnames":["Bershteyn"],"firstnames":["Marina"],"suffixes":[]},{"propositions":[],"lastnames":["Hayashi"],"firstnames":["Yohei"],"suffixes":[]},{"propositions":[],"lastnames":["Desachy"],"firstnames":["Guillaume"],"suffixes":[]},{"propositions":[],"lastnames":["Hsiao"],"firstnames":["Edward","C"],"suffixes":[]},{"propositions":[],"lastnames":["Sami"],"firstnames":["Salma"],"suffixes":[]},{"propositions":[],"lastnames":["Tsang"],"firstnames":["Kathryn","M"],"suffixes":[]},{"propositions":[],"lastnames":["Weiss"],"firstnames":["Lauren","A"],"suffixes":[]},{"propositions":[],"lastnames":["Kriegstein"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Yamanaka"],"firstnames":["Shinya"],"suffixes":[]},{"propositions":[],"lastnames":["Wynshaw-Boris"],"firstnames":["Anthony"],"suffixes":[]}],"abstract":"Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of 'chromosome therapy' to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.","journal":"Nature","volume":"507","number":"7490","pages":"99–103","month":"January","year":"2014","language":"en","bibtex":"@ARTICLE{Bershteyn2014-ih,\n title = \"Cell-autonomous correction of ring chromosomes in human induced\n pluripotent stem cells\",\n author = \"Bershteyn, Marina and Hayashi, Yohei and Desachy, Guillaume and\n Hsiao, Edward C and Sami, Salma and Tsang, Kathryn M and Weiss,\n Lauren A and Kriegstein, Arnold R and Yamanaka, Shinya and\n Wynshaw-Boris, Anthony\",\n abstract = \"Ring chromosomes are structural aberrations commonly associated\n with birth defects, mental disabilities and growth retardation.\n Rings form after fusion of the long and short arms of a\n chromosome, and are sometimes associated with large terminal\n deletions. Owing to the severity of these large aberrations that\n can affect multiple contiguous genes, no possible therapeutic\n strategies for ring chromosome disorders have been proposed.\n During cell division, ring chromosomes can exhibit unstable\n behaviour leading to continuous production of aneuploid progeny\n with low viability and high cellular death rate. The overall\n consequences of this chromosomal instability have been largely\n unexplored in experimental model systems. Here we generated human\n induced pluripotent stem cells (iPSCs) from patient fibroblasts\n containing ring chromosomes with large deletions and found that\n reprogrammed cells lost the abnormal chromosome and duplicated\n the wild-type homologue through the compensatory uniparental\n disomy (UPD) mechanism. The karyotypically normal iPSCs with\n isodisomy for the corrected chromosome outgrew co-existing\n aneuploid populations, enabling rapid and efficient isolation of\n patient-derived iPSCs devoid of the original chromosomal\n aberration. Our results suggest a fundamentally different\n function for cellular reprogramming as a means of 'chromosome\n therapy' to reverse combined loss-of-function across many genes\n in cells with large-scale aberrations involving ring structures.\n In addition, our work provides an experimentally tractable human\n cellular system for studying mechanisms of chromosomal number\n control, which is of critical relevance to human development and\n disease.\",\n journal = \"Nature\",\n volume = 507,\n number = 7490,\n pages = \"99--103\",\n month = jan,\n year = 2014,\n language = \"en\"\n}\n\n","author_short":["Bershteyn, M.","Hayashi, Y.","Desachy, G.","Hsiao, E. C","Sami, S.","Tsang, K. M","Weiss, L. A","Kriegstein, A. 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