RING1B O-GlcNAcylation regulates gene targeting of polycomb repressive complex 1 in human embryonic stem cells
RING1B O-GlcNAcylation regulates gene targeting of polycomb repressive complex 1 in human embryonic stem cells
复制标题
RING1B O-GlcNAcylation调节人类胚胎干细胞中多聚酶抑制复合体1的基因靶向性
DOI：
10.1016/j.scr.2015.06.007
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发表时间：
2015-07-01
影响因子：
1.2
通讯作者：
Choo, Andre Boon-Hwa
中科院分区：
文献类型：
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作者：
Maurya, Julien Jean Pierre;El Farran, Chadi A.;Choo, Andre Boon-Hwa
O-连接-N-乙酰氨基葡萄糖(O-GlcNAc)在翻译后修饰和调节数千种参与各种细胞机制的蛋白质。最近，O-GlcNAc与人胚胎干细胞(HESC)的分化有关，但O-GlcNAc蛋白调控hESC的特性和功能尚不清楚。在这里，我们首先发现了O-GlcNAc修饰的人类干细胞调节因子，如hnRNP K，HP1 Gamma，特别是Ring1b/RNF2。此后，我们的工作集中在Ring1b上，它是多梳抑制复合体1(Prc1)的催化亚单位，是一种主要的表观遗传抑制因子，对多能性的维持和分化至关重要。通过点突变，我们发现T-250/S-251和S-278Ring1b残基含有O-GlcNAc，而T-250/S-251的O-GlcN酰化在分化过程中降低。根据我们的芯片测序结果，O-GlcNAc似乎调节Ring1b-DNA结合。非O-GlcNacylated Ring1b被发现在细胞周期基因附近富含，而O-GlcNacylated Ring1b似乎优先在神经元基因附近富含。我们的数据提示，在hESC分化过程中，Ring1b O-GlcN酰化水平的降低可能使Prc1改变其靶点以诱导神经元分化。总之，我们证明O-GlcNAc修饰和调节一个重要的表观遗传学工具Ring1b，这可能有助于hESC多能性的维持和分化。(C)2015年提交人。爱思唯尔出版公司(Elsevier B.V.)
O-linked-N-acetylglucosamine (O-GlcNAc) post-translationally modifies and regulates thousands of proteins involved in various cellular mechanisms. Recently, O-GlcNAc has been linked to human embryonic stem cells (hESC) differentiation, however the identity and function of O-GlcNAc proteins regulating hESC remain unknown. Here, we firstly identified O-GlcNAc modified human stem cell regulators such as hnRNP K, HP1 gamma, and especially RING1B/RNF2. Thereafter, we focused our work on RING1B which is the catalytic subunit of the polycomb repressive complex 1 (PRC1) a major epigenetic repressor essential for pluripotency maintenance and differentiation. By point-mutation, we show that T-250/S-251 and S-278 RING1B residues are bearing O-GlcNAc, and that T-250/S-251 O-GlcNAcylation decreases during differentiation. O-GlcNAc seems to regulate RING1B-DNA binding as suggested by our ChIP-sequencing results. Non-O-GlcNAcylated RING1B is found to be enriched near cell cycle genes whereas O-GlcNAcylated RING1B seems preferentially enriched near neuronal genes. Our data suggest that during hESC differentiation, the decrease of RING1B O-GlcNAcylation might enable PRC1 to switch its target to induce neuron differentiation. Overall, we demonstrate that O-GlcNAc modifies and regulates an essential epigenetic tool, RING1B, which may contribute to hESC pluripotency maintenance and differentiation. (C) 2015 The Authors. Published by Elsevier B.V.