PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome
PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome
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DOI：
10.1038/s41375-020-01023-1
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发表时间：
2020-08-21
期刊：
影响因子：
11.4
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
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作者：
Aoyama, Kazumasa;Shinoda, Daisuke;Iwama, Atsushi
EZH1和EZH2是多梳抑制复合体(PRC)2的酶组分，它催化组蛋白H3K27三甲基化(H3K27me3)抑制PRC2靶基因的转录。我们之前曾报道，Ezh2(Delta/Delta)缺失导致小鼠的骨髓增生异常综合征(MDS)样疾病。我们在此证明了Ezh1(+/-)Ezh2(Delta/Delta)基因缺失导致的严重的PRC2功能不全会导致晚期红细胞生成障碍，并伴有分化障碍和红细胞凋亡增加。在Ezh1(+/-)Ezh2(Delta/Delta)小鼠中，P53被核糖体生物合成障碍所激活，但在Ezh1(+/-)Ezh2(Delta/Delta)小鼠的造血干或祖细胞中不被激活。在Ezh1(+/-)Ezh2(Delta/Delta)红系小鼠中，编码p19(Arf)的主要PRC2靶点CDnu2a被去抑制，它通过抑制MDM2 E3泛素连接酶来激活P53。CDKN2a和asP53基因的缺失挽救了Ezh1(+/-)Ezh2(Delta/Delta)小鼠的红细胞生成障碍，表明PrC2不足通过抑制CDKN2a而导致P53依赖性的红细胞生成异常。由于PRC2功能不全常与MDS的发病机制有关，本研究结果提示，在PRC2功能不全的情况下，MDS存在P53依赖性的红细胞生成障碍。
EZH1 and EZH2 are enzymatic components of polycomb repressive complex (PRC) 2, which catalyzes histone H3K27 tri-methylation (H3K27me3) to repress the transcription of PRC2 target genes. We previously reported that the hematopoietic cell-specificEzh2deletion (Ezh2(Delta/Delta)) induced a myelodysplastic syndrome (MDS)-like disease in mice. We herein demonstrated that severe PRC2 insufficiency induced by the deletion of one alleleEzh1inEzh2-deficient mice (Ezh1(+/-)Ezh2(Delta/Delta)) caused advanced dyserythropoiesis accompanied by a differentiation block and enhanced apoptosis in erythroblasts. p53, which is activated by impaired ribosome biogenesis in del(5q) MDS, was specifically activated in erythroblasts, but not in hematopoietic stem or progenitor cells inEzh1(+/-)Ezh2(Delta/Delta)mice.Cdkn2a, a major PRC2 target encoding p19(Arf), which activates p53 by inhibiting MDM2 E3 ubiquitin ligase, was de-repressed inEzh1(+/-)Ezh2(Delta/Delta)erythroblasts. The deletion ofCdkn2aas well asp53rescued dyserythropoiesis inEzh1(+/-)Ezh2(Delta/Delta)mice, indicating that PRC2 insufficiency caused p53-dependent dyserythropoiesis via the de-repression ofCdkn2a. Since PRC2 insufficiency is often involved in the pathogenesis of MDS, the present results suggest that p53-dependent dyserythropoiesis manifests in MDS in the setting of PRC2 insufficiency.