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...
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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. |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0264965</identifier><identifier>PMID: 35271616</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Aneuploidy ; Biology ; Biology and Life Sciences ; Birth defects ; Births ; Care and treatment ; Chromosome 21 ; Chromosomes ; Cloning ; Congenital defects ; Cytogenetics ; Disorders ; Down syndrome ; Down Syndrome - genetics ; Down's syndrome ; Embryos ; Fibroblasts ; Genomes ; Humans ; Hybridization ; Induced Pluripotent Stem Cells ; Karyotypes ; Life expectancy ; Medicine ; Medicine and Health Sciences ; Meiosis ; Mosaicism ; Nucleotides ; Patients ; Polymorphism ; Radiation ; Research and Analysis Methods ; Single-nucleotide polymorphism ; Skin ; Trisomy ; Trisomy - genetics ; Uniparental Disomy</subject><ispartof>PloS one, 2022-03, Vol.17 (3), p.e0264965-e0264965</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Akutsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 Akutsu et al 2022 Akutsu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-daa664a47c9569af0afb7632d38a90b6a7a292c80e48c3c02b05b5512a83d0d33</citedby><cites>FETCH-LOGICAL-c758t-daa664a47c9569af0afb7632d38a90b6a7a292c80e48c3c02b05b5512a83d0d33</cites><orcidid>0000-0002-1097-0647 ; 0000-0002-6978-4136 ; 0000-0001-5294-081X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912248/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912248/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35271616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>El-Maarri, Osman</contributor><creatorcontrib>Akutsu, Silvia Natsuko</creatorcontrib><creatorcontrib>Miyamoto, Tatsuo</creatorcontrib><creatorcontrib>Oba, Daiju</creatorcontrib><creatorcontrib>Tomioka, Keita</creatorcontrib><creatorcontrib>Ochiai, Hiroshi</creatorcontrib><creatorcontrib>Ohashi, Hirofumi</creatorcontrib><creatorcontrib>Matsuura, Shinya</creatorcontrib><title>iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. 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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. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>35271616</pmid><doi>10.1371/journal.pone.0264965</doi><tpages>e0264965</tpages><orcidid>https://orcid.org/0000-0002-1097-0647</orcidid><orcidid>https://orcid.org/0000-0002-6978-4136</orcidid><orcidid>https://orcid.org/0000-0001-5294-081X</orcidid><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Analysis Aneuploidy Biology Biology and Life Sciences Birth defects Births Care and treatment Chromosome 21 Chromosomes Cloning Congenital defects Cytogenetics Disorders Down syndrome Down Syndrome - genetics Down's syndrome Embryos Fibroblasts Genomes Humans Hybridization Induced Pluripotent Stem Cells Karyotypes Life expectancy Medicine Medicine and Health Sciences Meiosis Mosaicism Nucleotides Patients Polymorphism Radiation Research and Analysis Methods Single-nucleotide polymorphism Skin Trisomy Trisomy - genetics Uniparental Disomy |
title | iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T05%3A17%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=iPSC%20reprogramming-mediated%20aneuploidy%20correction%20in%20autosomal%20trisomy%20syndromes&rft.jtitle=PloS%20one&rft.au=Akutsu,%20Silvia%20Natsuko&rft.date=2022-03-10&rft.volume=17&rft.issue=3&rft.spage=e0264965&rft.epage=e0264965&rft.pages=e0264965-e0264965&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0264965&rft_dat=%3Cgale_plos_%3EA696333937%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2637999549&rft_id=info:pmid/35271616&rft_galeid=A696333937&rft_doaj_id=oai_doaj_org_article_6cbbb1d1ff734ff596206875dc9c2555&rfr_iscdi=true |