Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification

Tatsuo Ito,Mark T Bedford,Kenji Yoshida,Megumi Tsuchiya,Neelu Yadav,Takayuki Furumatsu,Satoshi Yamashita,Noboru Taniguchi,Megumi Hashimoto,Martin Lotz,Jaeho Lee,Hiroshi Asahara,Toshifumi Ozaki

doi:10.1186/1471-213x-9-47

Abstract

BackgroundChondrogenesis and subsequent endochondral ossification are processes tightly regulated by the transcription factor Sox9 (SRY-related high mobility group-Box gene 9), but molecular mechanisms underlying this activity remain unclear. Here we report that coactivator-associated arginine methyltransferase 1 (CARM1) regulates chondrocyte proliferation via arginine methylation of Sox9.ResultsCARM1-null mice display delayed endochondral ossification and decreased chondrocyte proliferation. Conversely, cartilage development of CARM1 transgenic mice was accelerated. CARM1 specifically methylates Sox9 at its HMG domain in vivo and in vitro. Arg-methylation of Sox9 by CARM1 disrupts interaction of Sox9 with beta-catenin, regulating Cyclin D1 expression and cell cycle progression of chondrocytes.ConclusionThese results establish a role for CARM1 as an important regulator of chondrocyte proliferation during embryogenesis.

Highlights

Chondrogenesis and subsequent endochondral ossification are processes tightly regulated by the transcription factor Sox9 (SRY-related high mobility group-Box gene 9), but molecular mechanisms underlying this activity remain unclear
coactivatorassociated arginine methyltransferase 1 (CARM1) belongs to a family of arginine-specific protein methyltransferases (PRMTs), which includes at least eight members (PRMT1-8) [8]
In situ hybridization (ISH) of, Col2a1, Col10a1, Bone Sialoprotein (BSP), Osteopontin (Op), Osteocalcin (Oc) and Runx2 in mutant embryos supported the conclusion that endochondral bone formation was significantly delayed (Additional file 1)

Summary

Introduction

Chondrogenesis and subsequent endochondral ossification are processes tightly regulated by the transcription factor Sox (SRY-related high mobility group-Box gene 9), but molecular mechanisms underlying this activity remain unclear. We report that coactivatorassociated arginine methyltransferase 1 (CARM1) regulates chondrocyte proliferation via arginine methylation of Sox. The precise patterning of the developing skeletal framework relies on the appropriate control of chondrogenesis, a multistep process during which mesenchymal cells differentiate into chondrocytes[1,2]. This process is tightly regulated by transcription factors, including Sox9 [3,4,5,6]. CARM1 belongs to a family of arginine-specific protein methyltransferases (PRMTs), which includes at least eight members (PRMT1-8) [8]. After recruitment to promoters of steroid-responsive genes, CARM1 methylates specific residues (Arg and Arg26) at the Nterminus of histone H3 resulting in transcriptional activation[11,12]

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