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iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes
Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. They are mostly derived from chromosome non-disjunction in maternal meiosis, and the extra trisomic chromosome can cause several congenital malformations. Various genes on the trisomic chromosomes are intricately involved...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912248/ https://www.ncbi.nlm.nih.gov/pubmed/35271616 http://dx.doi.org/10.1371/journal.pone.0264965 |
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author | Akutsu, Silvia Natsuko Miyamoto, Tatsuo Oba, Daiju Tomioka, Keita Ochiai, Hiroshi Ohashi, Hirofumi Matsuura, Shinya |
author_facet | Akutsu, Silvia Natsuko Miyamoto, Tatsuo Oba, Daiju Tomioka, Keita Ochiai, Hiroshi Ohashi, Hirofumi Matsuura, Shinya |
author_sort | Akutsu, Silvia Natsuko |
collection | PubMed |
description | Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. They are mostly derived from chromosome non-disjunction in maternal meiosis, and the extra trisomic chromosome can cause several congenital malformations. Various genes on the trisomic chromosomes are intricately involved in the development of disease, and fundamental treatments have not yet been established. However, chromosome therapy has been developed to correct the extra chromosome in cultured patient cells, and it was recently reported that during reprogramming into iPSCs, fibroblasts from a Down syndrome patient lost the extra chromosome 21 due to a phenomenon called trisomy-biased chromosome loss. To gain preliminary insights into the underlying mechanism of trisomy rescue during the early stages of reprogramming, we reprogrammed skin fibroblasts from patients with trisomy syndromes 21, 18, 13, and 9 to iPSC, and evaluated the genomes of the individual iPSC colonies by molecular cytogenetic techniques. We report the spontaneous correction from trisomy to disomy upon cell reprogramming in at least one cell line examined from each of the trisomy syndromes, and three possible combinations of chromosomes were selected in the isogenic trisomy-rescued iPSC clones. Single nucleotide polymorphism analysis showed that the trisomy-rescued clones exhibited either heterodisomy or segmental uniparental isodisomy, ruling out the possibility that two trisomic chromosomes were lost simultaneously and the remaining one was duplicated, suggesting instead that one trisomic chromosome was lost to generate disomic cells. These results demonstrated that trisomy rescue may be a phenomenon with random loss of the extra chromosome and subsequent selection for disomic iPSCs, which is analogous to the karyotype correction in early preimplantation embryos. Our finding is relevant for elucidating the mechanisms of autonomous karyotype correction and future application in basic and clinical research on aneuploidy disorders. |
format | Online Article Text |
id | pubmed-8912248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-89122482022-03-11 iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes Akutsu, Silvia Natsuko Miyamoto, Tatsuo Oba, Daiju Tomioka, Keita Ochiai, Hiroshi Ohashi, Hirofumi Matsuura, Shinya PLoS One Research Article Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. They are mostly derived from chromosome non-disjunction in maternal meiosis, and the extra trisomic chromosome can cause several congenital malformations. Various genes on the trisomic chromosomes are intricately involved in the development of disease, and fundamental treatments have not yet been established. However, chromosome therapy has been developed to correct the extra chromosome in cultured patient cells, and it was recently reported that during reprogramming into iPSCs, fibroblasts from a Down syndrome patient lost the extra chromosome 21 due to a phenomenon called trisomy-biased chromosome loss. To gain preliminary insights into the underlying mechanism of trisomy rescue during the early stages of reprogramming, we reprogrammed skin fibroblasts from patients with trisomy syndromes 21, 18, 13, and 9 to iPSC, and evaluated the genomes of the individual iPSC colonies by molecular cytogenetic techniques. We report the spontaneous correction from trisomy to disomy upon cell reprogramming in at least one cell line examined from each of the trisomy syndromes, and three possible combinations of chromosomes were selected in the isogenic trisomy-rescued iPSC clones. Single nucleotide polymorphism analysis showed that the trisomy-rescued clones exhibited either heterodisomy or segmental uniparental isodisomy, ruling out the possibility that two trisomic chromosomes were lost simultaneously and the remaining one was duplicated, suggesting instead that one trisomic chromosome was lost to generate disomic cells. These results demonstrated that trisomy rescue may be a phenomenon with random loss of the extra chromosome and subsequent selection for disomic iPSCs, which is analogous to the karyotype correction in early preimplantation embryos. Our finding is relevant for elucidating the mechanisms of autonomous karyotype correction and future application in basic and clinical research on aneuploidy disorders. Public Library of Science 2022-03-10 /pmc/articles/PMC8912248/ /pubmed/35271616 http://dx.doi.org/10.1371/journal.pone.0264965 Text en © 2022 Akutsu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Akutsu, Silvia Natsuko Miyamoto, Tatsuo Oba, Daiju Tomioka, Keita Ochiai, Hiroshi Ohashi, Hirofumi Matsuura, Shinya iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title_full | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title_fullStr | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title_full_unstemmed | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title_short | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
title_sort | ipsc reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912248/ https://www.ncbi.nlm.nih.gov/pubmed/35271616 http://dx.doi.org/10.1371/journal.pone.0264965 |
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