Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes
Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes
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DOI：
10.1038/ncomms3850
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发表时间：
2013-11-01
影响因子：
16.6
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Hata, Kenji;Takashima, Rikako;Yoneda, Toshiyuki
组蛋白修饰是表观遗传调控的关键步骤，是生物学事件的重要调节因子。Sox 9是一种对软骨内骨化至关重要的转录因子;然而，其表观遗传调控的证据仍然难以捉摸。在这里，我们确定AT丰富的互动结构域5 b（Arid 5 b）作为Sox 9的转录共调节。Arid 5 b与Sox 9物理结合并协同诱导软骨形成。Arid 5 b（-/-）小鼠的生长因延迟的软骨内骨化而延迟。Sox 9依赖性软骨形成在Arid 5 b缺陷细胞中减弱。Arid 5 b将组蛋白赖氨酸去甲基化酶Phf 2募集到Sox 9靶基因的启动子区域，并刺激这些基因的H3 K9 me 2去甲基化。在软骨形成标记基因的启动子中，H3 K9 me 2水平在Arid 5 b（-/-）软骨细胞中增加。最后，我们表明，Phf 2敲低抑制Sox 9诱导的软骨细胞分化。我们的研究结果建立了骨骼发育的表观基因组机制，Arid 5 b通过促进Phf 2介导的Sox 9调控的软骨形成基因启动子的组蛋白去甲基化来促进软骨形成。
Histone modification, a critical step for epigenetic regulation, is an important modulator of biological events. Sox9 is a transcription factor critical for endochondral ossification; however, proof of its epigenetic regulation remains elusive. Here we identify AT-rich interactive domain 5b (Arid5b) as a transcriptional co-regulator of Sox9. Arid5b physically associates with Sox9 and synergistically induces chondrogenesis. Growth of Arid5b(-/-) mice is retarded with delayed endochondral ossification. Sox9-dependent chondrogenesis is attenuated in Arid5b-deficient cells. Arid5b recruits Phf2, a histone lysine demethylase, to the promoter region of Sox9 target genes and stimulates H3K9me2 demethylation of these genes. In the promoters of chondrogenic marker genes, H3K9me2 levels are increased in Arid5b(-/-) chondrocytes. Finally, we show that Phf2 knockdown inhibits Sox9-induced chondrocyte differentiation. Our findings establish an epigenomic mechanism of skeletal development, whereby Arid5b promotes chondrogenesis by facilitating Phf2-mediated histone demethylation of Sox9-regulated chondrogenic gene promoters.