JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling.
JARID2 and the PRC2 complex regulate skeletal muscle differentiation through regulation of canonical Wnt signaling.
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DOI：
10.1186/s13072-018-0217-x
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发表时间：
2018-08-17
影响因子：
3.9
通讯作者：
Davie J
中科院分区：
文献类型：
--
作者：
Adhikari A;Davie J
JARID 2是多梳抑制复合物2（PRC 2）的非催化成员，已知PRC 2调节胚胎干细胞中的发育靶基因。在这里，我们提供了机制的洞察Wnt信号的调制JARID 2在小鼠骨骼肌分化。我们发现JARID 2在增殖的成肌细胞中表达，但在肌肉分化后下调。出乎意料的是，JARID 2或PRC 2复合物的催化亚基EZH 2的消耗抑制了分化，表明JARID 2和PRC 2复合物是启动该过程所必需的。促进分化所需的生肌调节因子MYOD和MYOG的表达在不存在JARID 2的情况下下调，即使在两个启动子上观察到组蛋白H3赖氨酸27（H3 K27 me 3）的甲基化降低。我们发现Wnt信号通路的激活上调MYOD并恢复分化。在JARID 2缺失的细胞中，Wnt通路的激活导致β-连环蛋白易位到细胞核，在那里它结合并激活Myod 1启动子。我们发现，Wnt拮抗剂SFRP 1在JARID 2不存在的情况下高度上调，并且是JARID 2和PRC 2复合物的直接靶标。SFRP 1的异位表达阻断了MYOD和晚期肌肉基因的表达，并抑制了β-catenin向细胞核的移位。最后，我们发现JARID 2和SFRP 1在黑色素瘤中呈负相关，证实JARID 2介导的SFRP 1抑制延伸到骨骼肌之外，并在许多细胞系统中具有重要意义，包括癌症。我们发现JARID 2和PRC 2复合物通过直接抑制Wnt拮抗剂调节Wnt信号传导来调节肌肉分化。本文的在线版本（10.1186/s13072-018-0217-x）包含补充材料，可供授权用户使用。
JARID2 is a non-catalytic member of the polycomb repressive complex 2 (PRC2), which is known to regulate developmental target genes in embryonic stem cells. Here, we provide mechanistic insight into the modulation of Wnt signaling by JARID2 during murine skeletal muscle differentiation. We show that JARID2 is expressed in proliferating myoblasts, but downregulated upon muscle differentiation. Unexpectedly, depletion of JARID2 or the catalytic subunit of the PRC2 complex, EZH2, inhibited differentiation, suggesting that JARID2 and the PRC2 complex are required to initiate this process. Expression of the myogenic regulatory factors required to promote differentiation, MYOD and MYOG, was downregulated in the absence of JARID2, even though decreases in the methylation of histone H3 lysine 27 (H3K27me3) were observed on both promoters. We found that activation of the Wnt signaling pathway upregulated MYOD and restored differentiation. Activation of the Wnt pathway in JARID2 depleted cells caused β-catenin to translocate to the nucleus, where it bound to and activated the Myod1 promoter. We show that the Wnt antagonist SFRP1 is highly upregulated in the absence of JARID2 and is a direct target of JARID2 and the PRC2 complex. Ectopic expression of SFRP1 blocked MYOD and late muscle gene expression and inhibited the translocation of β-catenin to the nucleus. Finally, we show that JARID2 and SFRP1 are inversely correlated in melanoma, confirming that the JARID2-mediated repression of SFRP1 extends beyond skeletal muscle and has important implications in many cellular systems, including cancer. We show that JARID2 and the PRC2 complex regulate muscle differentiation by modulating Wnt signaling through the direct repression of Wnt antagonists. The online version of this article (10.1186/s13072-018-0217-x) contains supplementary material, which is available to authorized users.
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