title: Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.
abstract: Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Munetsugu
authors.initials: M
authors.lastname: Hara
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Mitsumasu
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Igata
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.affiliation: Cardiovascular Research Institute, Kurume University, Kurume, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minami
authors.affiliation: Cardiovascular Research Institute, Kurume University, Kurume, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.affiliation: Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Okayama
authors.affiliation: Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okabe
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Internal Medicine, Asahi University School of Dentistry, Gifu, Japan.
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan [3] Department of Gene Therapy and Regenerative Medicine, Advanced Therapeutics Course, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kosai
authors.affiliation: Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yushiro
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: 1] Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases [2] Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Toyojiro
authors.initials: T
authors.lastname: Matsuishi
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D018899:CpG Islands; D019175:DNA Methylation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D009218:Myosins