Epigenomic regulation in congenital anomaly syndromes

2015 Fiscal Year Final Research Report

• Project/Area Number: 26670490
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学(系)研究科(研究院), 教授 (80332500)
• Co-Investigator(Kenkyū-buntansha): MATSUBARA Yoichi 国立研究開発法人国立成育医療研究センター, 研究所, 所長 (00209602) ; NIIHORI Tetsuya 東北大学, 大学院医学系研究科, 准教授 (40436134) ; INOUE Shinichi 東北大学, 大学院医学系研究科, 助教 (70622091)
• Research Collaborator: YAOITA Masako 東北大学, 大学院医学系研究科 ; OBA Daiju 東北大学, 大学院医学系研究科 ; NISHIYAMA Ayumi 東北大学, 大学院医学系研究科 ; UMEKI Ikumi 東北大学, 大学院医学系研究科 ; TAKAHARA Shingo 東北大学, 大学院医学系研究科
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: ヌーナン症候群 / RAS / エピゲノム

Outline of Final Research Achievements

In this study, we analyzed genes that are associated with epigenetic modifications in patients, who are clinically diagnosed as having RASopathies, and identified pathogenic mutations in three affected individuals. We generated a knock-in mice expressing a Braf p.Q241R mutation, as a model mice for CFC syndrome. Treatment with a MEK inhibitor, PD0325901, and a histone H3K27 demethylase inhibitor, GSK-J4, have rescued embryonic lethality in BrafQ241R/+ mice. To explore the mechanisms of efficacy in PD0325901 and GSK-J4 co-treatment, we examined mRNA and protein levels of histone H3K27 methylase and histone H3K27 demethylases in heart tissues from control and BrafQ241R/+ embryos. Further analysis on methylation profiling of H3K27 in each gene will clarify the mechanisms why co-treatment of PD0325901 and GSK-J4 rescued the embryonic lethality in in BrafQ241R/+ mice.

Free Research Field

分子遺伝学