Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome.
Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome.
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DOI：
10.1016/j.isci.2018.10.008
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发表时间：
2018-11-30
期刊：
影响因子：
5.8
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Aoyama K;Oshima M;Koide S;Suzuki E;Mochizuki-Kashio M;Kato Y;Tara S;Shinoda D;Hiura N;Nakajima-Takagi Y;Sashida G;Iwama A
多梳抑制复合物（PRC）2通过组蛋白H3 K27三甲基化（H3 K27 me 3）抑制转录。我们先前报道了造血细胞特异性缺失Ezh 2（编码PRC 2酶）诱导小鼠骨髓增生异常综合征（MDS），而同时Ezh 1缺失耗尽造血干细胞和祖细胞（HSPC）。我们在此证明了仅具有一个Ezh 1等位基因（Ezh 1 +/-Ezh 2 Δ/Δ）的小鼠维持HSPC。染色质免疫沉淀序列分析显示，残留的PRC 2优先靶向HSPC中具有高水平H3 K27 me 3和H2 AK 119单泛素化（H2 AK 119 ub 1）的基因（称为Ezh 1核心靶基因），这些基因主要是发育调节因子，并在Ezh 1 +/-Ezh 2 Δ/Δ HSPC中维持H3 K27 me 3水平。即使在Ezh 1和Ezh 2完全耗尽后，H2 AK 119 ub 1水平也在很大程度上保留，并且只有最小数量的Ezh 1核心靶点被去抑制。这些结果表明，标记有高水平H3 K27 me 3和H2 AK 119 ub 1的基因是HSPC以及MDS干细胞中多梳复合物的核心靶标。Ezh 1的一个等位基因足以维持自我更新的HSC和MDS干细胞Ezh 1核心靶标在HSPC中标记有高水平的H3 K27 me 3和H2 AK 119 ub 1 Ezh 1核心靶标大多是二价发育调节剂，对HSC至关重要生物科学;遗传学;分子生物学;免疫学;细胞生物学;发育生物学
Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic-cell-specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, whereas the concurrent Ezh1 deletion depleted hematopoietic stem and progenitor cells (HSPCs). We herein demonstrated that mice with only one Ezh1 allele (Ezh1+/-Ezh2Δ/Δ) maintained HSPCs. A chromatin immunopreciptation sequence analysis revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitination (H2AK119ub1) in HSPCs (designated as Ezh1 core target genes), which were mostly developmental regulators, and maintained H3K27me3 levels in Ezh1+/-Ezh2Δ/Δ HSPCs. Even upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of Ezh1 core targets were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of polycomb complexes in HSPCs as well as MDS stem cells. One allele of Ezh1 is enough to maintain self-renewing HSCs and MDS stem cells Ezh1 core targets are marked with high levels of H3K27me3 and H2AK119ub1 in HSPCs Ezh1 core targets are mostly bivalent developmental regulators and critical for HSCs Biological Sciences; Genetics; Molecular Biology; Immunology; Cell Biology; Developmental Biology
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DOI：
10.1084/jem.20131144
发表时间：
2013-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Muto T;Sashida G;Oshima M;Wendt GR;Mochizuki-Kashio M;Nagata Y;Sanada M;Miyagi S;Saraya A;Kamio A;Nagae G;Nakaseko C;Yokote K;Shimoda K;Koseki H;Suzuki Y;Sugano S;Aburatani H;Ogawa S;Iwama A
通讯作者：
Iwama A
体细胞突变改变生发中心起源的滤泡性和弥漫性大 B 细胞淋巴瘤中的 EZH2 (Tyr641)。
影响因子：
30.8
作者：
Morin, Ryan D.;Johnson, Nathalie A.;Severson, Tesa M.;Mungall, Andrew J.;An, Jianghong;Goya, Rodrigo;Paul, Jessica E.;Boyle, Merrill;Woolcock, Bruce W.;Kuchenbauer, Florian;Yap, Damian;Humphries, R. Keith;Griffith, Obi L.;Shah, Sohrab;Zhu, Henry;Kimbara, Michelle;Shashkin, Pavel;Charlot, Jean F.;Tcherpakov, Marianna;Corbett, Richard;Tam, Angela;Varhol, Richard;Smailus, Duane;Moksa, Michelle;Zhao, Yongjun;Delaney, Allen;Qian, Hong;Birol, Inanc;Schein, Jacqueline;Moore, Richard;Holt, Robert;Horsman, Doug E.;Connors, Joseph M.;Jones, Steven;Aparicio, Samuel;Hirst, Martin;Gascoyne, Randy D.;Marra, Marco A.
通讯作者：
Marra, Marco A.
EZH1和EZH2通过不同的机制保持抑制性染色质。
影响因子：
16
作者：
Margueron, Raphael;Li, Guohong;Sarma, Kavitha;Blais, Alexandre;Zavadil, Jiri;Woodcock, Christopher L.;Dyniacht, Brian D.;Reinberg, Danny
通讯作者：
Reinberg, Danny
影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1038/nrm4067
发表时间：
2015-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Blackledge NP;Rose NR;Klose RJ
通讯作者：
Klose RJ