Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis
Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis
复制标题
DOI：
10.1038/s41375-021-01402-2
复制
发表时间：
2021-09
期刊：
影响因子：
11.4
通讯作者：
Daisuke Shinoda;Yaeko Nakajima-Takagi;M. Oshima;S. Koide;Kazumasa Aoyama;A. Saraya;H. Harada;Bahityar Rahmutulla;Atsushi Kaneda;K. Yamaguchi;Y. Furukawa;H. Koseki;K. Shimoda;Tomoaki Tanaka;G. Sashida;A. Iwama
中科院分区：
文献类型：
--
作者：
Daisuke Shinoda;Yaeko Nakajima-Takagi;M. Oshima;S. Koide;Kazumasa Aoyama;A. Saraya;H. Harada;Bahityar Rahmutulla;Atsushi Kaneda;K. Yamaguchi;Y. Furukawa;H. Koseki;K. Shimoda;Tomoaki Tanaka;G. Sashida;A. Iwama
多梳抑制复合体2(PRC2)是组蛋白H3在27位赖氨酸的三甲基化产物，在原发性骨髓纤维化中经常发现，它通过促进发育不良的巨核细胞的产生促进JAK2V617F诱导的小鼠骨髓纤维化的发展。多梳环指蛋白1(Pcgf1)是PRC1.1的一个组成部分，PRC1.1是一种非规范的Prc1，它使赖氨酸119位的H_2A(H_2AK119ub1)单糖化。我们在此研究了PRC1.1功能不全对骨髓纤维化的影响。JAK2V617F小鼠中Pcgf1基因的缺失强烈促进了致死性骨髓纤维化的发展，并伴有红系分化障碍。转录组和染色质免疫沉淀序列分析表明，在Pcgf1缺陷的JAK2V617F造血祖细胞中，PRC1.1靶基因的表达下调，并显示Hoxacluster基因是直接靶标。JAK2V617F造血干/祖细胞(HSPC)中Pcgf1基因的缺失和Hoxa9基因的过表达恢复了JAK2V617F祖细胞的抑制增殖。Hoxa9基因的过表达也增强了JAK2V617F介导的骨髓纤维化。在PRC2缺失的JAK2V617F HSPC中，PRC2靶基因的表达在缺失Pcgf1的JAK2V617F HSPC中变化不大。本研究结果揭示了PRC1.1在骨髓纤维化中的肿瘤抑制作用，提示PRC1.1缺陷与PRC2缺陷在骨髓纤维化的发病机制中具有不同的影响。
Insufficiency of polycomb repressive complex 2 (PRC2), which trimethylates histone H3 at lysine 27, is frequently found in primary myelofibrosis and promotes the development of JAK2V617F-induced myelofibrosis in mice by enhancing the production of dysplastic megakaryocytes. Polycomb group ring finger protein 1 (Pcgf1) is a component of PRC1.1, a non-canonical PRC1 that monoubiquitylates H2A at lysine 119 (H2AK119ub1). We herein investigated the impact of PRC1.1 insufficiency on myelofibrosis. The deletion ofPcgf1in JAK2V617F mice strongly promoted the development of lethal myelofibrosis accompanied by a block in erythroid differentiation. Transcriptome and chromatin immunoprecipitation sequence analyses showed the de-repression of PRC1.1 target genes inPcgf1-deficient JAK2V617F hematopoietic progenitors and revealedHoxacluster genes as direct targets. The deletion ofPcgf1in JAK2V617F hematopoietic stem and progenitor cells (HSPCs), as well as the overexpression of Hoxa9, restored the attenuated proliferation of JAK2V617F progenitors. The overexpression ofHoxa9also enhanced JAK2V617F-mediated myelofibrosis. The expression of PRC2 target genes identified in PRC2-insufficient JAK2V617F HSPCs was not largely altered inPcgf1-deleted JAK2V617F HSPCs. The present results revealed a tumor suppressor function for PRC1.1 in myelofibrosis and suggest that PRC1.1 insufficiency has a different impact from that of PRC2 insufficiency on the pathogenesis of myelofibrosis.