iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes.
iPSC reprogramming-mediated aneuploidy correction in autosomal trisomy syndromes.
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DOI：
10.1371/journal.pone.0264965
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Matsuura S
中科院分区：
文献类型：
--
作者：
Akutsu SN;Miyamoto T;Oba D;Tomioka K;Ochiai H;Ohashi H;Matsuura S
21、18和13三体是人类主要的常染色体非整倍性疾病。它们大多来源于母体减数分裂中染色体不分离，额外的三体染色体可导致多种先天畸形。三体染色体上的各种基因错综复杂地参与疾病的发展，基本的治疗方法尚未建立。然而，已经开发了染色体疗法来纠正培养的患者细胞中的额外染色体，最近有报道称，在重编程为iPSC的过程中，来自唐氏综合征患者的成纤维细胞由于一种称为三体偏向染色体丢失的现象而丢失了额外的21号染色体。为了初步了解在重编程的早期阶段三体拯救的潜在机制，我们将来自三体综合征21、18、13和9患者的皮肤成纤维细胞重编程为iPSC，并通过分子细胞遗传学技术评估单个iPSC集落的基因组。我们报告了在从每个三体综合征检查的至少一个细胞系中细胞重编程后从三体到二体性的自发校正，并且在等基因三体拯救的iPSC克隆中选择了三种可能的染色体组合。单核苷酸多态性分析表明，三体拯救的克隆表现出异二体性或节段单亲异二体性，排除了两个三体染色体同时丢失而剩下的一个被复制的可能性，这表明一个三体染色体丢失而产生二体细胞。这些结果表明，三体拯救可能是一种随机丢失额外染色体并随后选择二体iPSC的现象，这类似于早期植入前胚胎中的核型校正。我们的发现对于阐明自主核型校正的机制以及未来在非整倍体疾病的基础和临床研究中的应用具有重要意义。
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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影响因子：
5.2
作者：
WYLLIE, JP;WRIGHT, MJ;HUNTER, S
通讯作者：
HUNTER, S
影响因子：
4.6
作者：
Nikitina TV;Kashevarova AA;Gridina MM;Lopatkina ME;Khabarova AA;Yakovleva YS;Menzorov AG;Minina YA;Pristyazhnyuk IE;Vasilyev SA;Fedotov DA;Serov OL;Lebedev IN
通讯作者：
Lebedev IN
DOI：
10.1016/j.tig.2017.04.001
发表时间：
2017-07
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McCoy RC
通讯作者：
McCoy RC
影响因子：
16.6
作者：
Bolton H;Graham SJL;Van der Aa N;Kumar P;Theunis K;Fernandez Gallardo E;Voet T;Zernicka-Goetz M
通讯作者：
Zernicka-Goetz M
影响因子：
5.9
作者：
Baker, Duncan;Hirst, Adam J.;Gokhale, Paul J.;Juarez, Miguel A.;Williams, Steve;Wheeler, Mark;Bean, Kerry;Allison, Thomas F.;Moore, Harry D.;Andrews, Peter W.;Barbaric, Ivana
通讯作者：
Barbaric, Ivana