A patient-derived iPSC model revealed oxidative stress increases facioscapulohumeral muscular dystrophy-causative DUX4
| العنوان: | A patient-derived iPSC model revealed oxidative stress increases facioscapulohumeral muscular dystrophy-causative DUX4 |
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| المؤلفون: | Ichizo Nishino, Satomi Mitsuhashi, Ryoichi Matsuda, Mitsuru Sasaki-Honda, Akitsu Hotta, Tatsuya Jonouchi, Meni Arai, Hidetoshi Sakurai |
| المصدر: | Human Molecular Genetics |
| بيانات النشر: | Oxford University Press, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Chromosomal Proteins, Non-Histone, Induced Pluripotent Stem Cells, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, DUX4, Genetics, medicine, Facioscapulohumeral muscular dystrophy, Myocyte, Humans, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Regulation of gene expression, Homeodomain Proteins, Mutation, Muscle Cells, Skeletal muscle, General Medicine, medicine.disease, Chromatin, Muscular Dystrophy, Facioscapulohumeral, Cell biology, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, General Article, CRISPR-Cas Systems, Chromosomes, Human, Pair 4, 030217 neurology & neurosurgery, DNA Damage |
| الوصف: | Double homeobox 4 (DUX4), the causative gene of facioscapulohumeral muscular dystrophy (FSHD), is ectopically expressed in the skeletal muscle cells of FSHD patients because of chromatin relaxation at 4q35. The diminished heterochromatic state at 4q35 is caused by either large genome contractions [FSHD type 1 (FSHD1)] or mutations in genes encoding chromatin regulators, such as SMCHD1 [FSHD type 2 (FSHD2)]. However, the mechanism by which DUX4 expression is regulated remains largely unknown. Here, using a myocyte model developed from patient-derived induced pluripotent stem cells, we determined that DUX4 expression was increased by oxidative stress (OS), a common environmental stress in skeletal muscle, in both FSHD1 and FSHD2 myocytes. We generated FSHD2-derived isogenic control clones with SMCHD1 mutation corrected by clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated 9 (Cas9) and homologous recombination and found in the myocytes obtained from these clones that DUX4 basal expression and the OS-induced upregulation were markedly suppressed due to an increase in the heterochromatic state at 4q35. We further found that DNA damage response (DDR) was involved in OS-induced DUX4 increase and identified ataxia-telangiectasia mutated, a DDR regulator, as a mediator of this effect. Our results suggest that the relaxed chromatin state in FSHD muscle cells permits aberrant access of OS-induced DDR signaling, thus increasing DUX4 expression. These results suggest OS could represent an environmental risk factor that promotes FSHD progression. 酸化ストレスが顔面肩甲上腕型筋ジストロフィーの 原因遺伝子DUX4を増加させることを発見しました. 京都大学プレスリリース. 2018-09-07. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1ac58aba45fcab447f017825363abc4 http://europepmc.org/articles/PMC6240734 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f1ac58aba45fcab447f017825363abc4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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