Investigation of epigenetic therapeutic targets for musculoskeletal diseases

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04961
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Ehime University
• Principal Investigator: Yuuki Imai 愛媛大学, プロテオサイエンスセンター, 教授 (10423873)
• Co-Investigator(Renkei-kenkyūsha): Inoue Kazuki 愛媛大学, 学術支援センター, 助教 (60623725) ; Sakakibara Iori 愛媛大学, プロテオサイエンスセンター, 助教 (50734662)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: エピジェネティクス / 軟骨 / ゲノムワイド解析

Outline of Final Research Achievements

The physiological functions of Uhrf1 in skeletal tissues remain unclear. We show that limb mesenchymal cell-specific Uhrf1 conditional knockout mice (cKO) exhibit remarkably shortened long bones that have morphological deformities due to dysregulated chondrocyte differentiation and proliferation. Especially, Mmp13 expression was significantly increased in both mRNA and protein levels in cKO mice. Integrative analyses using RNA-seq and MBD-seq revealed that Uhrf1 deficiency decreased genome-wide DNA methylation and increased gene expression through reduced DNA methylation in the promoter regions of 28 genes, including Hspb1. Hspb1 knockdown in cKO chondrocytes can normalize abnormal expression of genes involved in chondrocyte differentiation such as Mmp13. These results indicate that Uhrf1 governs cell-type specific transcriptional regulation by controlling the genome-wide DNA methylation status and regulating consequent cell differentiation and skeletal maturation.

Free Research Field

整形外科