title: A Pair of Maternal Chromosomes Derived from Meiotic Nondisjunction in Trisomy 21 Affects Nuclear Architecture and Transcriptional Regulation.
abstract: Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to maintain the physiological balance of gene expression. However, it has not been clearly elucidated whether and how aberrant configuration of chromosomes affects gene activities. To investigate the effects of trisomy 21 on nuclear organisation and gene expression, we performed three-dimensional fluorescent imaging analysis of chromosome-edited human induced pluripotent stem cells (iPSCs), which enabled identification of the parental origin of the three copies of chromosome 21. We found that two copies of maternal chromosomes resulting from meiotic nondisjunction had a higher tendency to form an adjacent pair and were located relatively distant from the nuclear membrane, suggesting the conserved interaction between these homologous chromosomes. Transcriptional profiling of parental-origin-specific corrected disomy 21 iPSC lines indicated upregulated expression of the maternal alleles for a group of genes, which was accompanied by a fluctuating expression pattern. These results suggest the unique effects of a pair of maternal chromosomes in trisomy 21, which may contribute to the pathological phenotype.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.|Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, 102-0083, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Omori
authors.affiliation: Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, SOKENDAI (The Graduate University for Advanced Studies), Shonan Village, Hayama, Kanagawa, 240-0193, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanabe
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Banno
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Tsuji
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Nawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kawatani
authors.affiliation: Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Kokubu
authors.affiliation: Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Arahori
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan. ykitaba@ped.med.osaka-u.ac.jp.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Kitabatake
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000175:diagnosis* / Q000235:genetics*; D005786:Gene Expression Regulation; D018390:Gene Targeting; D056426:Genetic Loci; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D000072741:Maternal Inheritance; D008540:Meiosis; D009630:Nondisjunction, Genetic; D010641:Phenotype; D014158:Transcription, Genetic; D014314:Trisomy