The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function
The histone H2A deubiquitinase Usp16 regulates hematopoiesis and hematopoietic stem cell function
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DOI：
10.1073/pnas.1517041113
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发表时间：
2016-01-05
影响因子：
11.1
通讯作者：
Wang, Hengbin
中科院分区：
文献类型：
--
作者：
Gu, Yue;Jones, Amanda E.;Wang, Hengbin
表观遗传机制在造血和造血干细胞（HSC）功能中发挥着重要的调节作用。多梳抑制复合物1（PRC 1）的亚基，主要的组蛋白H2 A泛素连接酶，是至关重要的正常和病理性造血;然而，目前还不清楚的几个抵消H2 A去泛素化酶的功能沿着PRC 1控制H2 A泛素化（ubH 2A）水平和调节体内造血。本研究探讨了Usp 16在小鼠造血中的作用。骨髓中Usp 16的条件性缺失导致总体ubH 2A水平和致死率显著增加。Usp 16的缺失并没有改变HSC的数量，但与成熟和祖细胞群体的急剧减少，揭示了在管理HSC谱系承诺的作用。在HSC和祖细胞中的ChIP和RNA测序研究显示，Usp 16与许多重要的造血调节因子结合，并且Usp 16缺失改变了转录/染色体组织、免疫应答、造血/淋巴器官发育和髓样/白细胞分化中的基因表达。PRC 1亚基的敲低部分挽救了改变的基因表达，表明Usp 16和PRC 1相互平衡，以调节造血系统中的细胞ubH 2A水平和基因表达。我们进一步发现，敲低Cdkn 1a（p21 cip 1），一个Usp 16靶基因和调控基因，挽救了Usp 16缺失的HSC的细胞周期谱和分化缺陷。总的来说，这些研究将Usp 16鉴定为组蛋白H2 A去泛素化酶之一，其与H2 A泛素连接酶PRC 1协调以调节造血，并揭示Usp 16对细胞周期的调节是HSC分化的关键。
Epigenetic mechanisms play important regulatory roles in hematopoiesis and hematopoietic stem cell (HSC) function. Subunits of polycomb repressive complex 1 (PRC1), the major histone H2A ubiquitin ligase, are critical for both normal and pathological hematopoiesis; however, it is unclear which of the several counteracting H2A deubiquitinases functions along with PRC1 to control H2A ubiquitination (ubH2A) level and regulates hematopoiesis in vivo. Here we investigated the function of Usp16 in mouse hematopoiesis. Conditional deletion of Usp16 in bone marrow resulted in a significant increase of global ubH2A level and lethality. Usp16 deletion did not change HSC number but was associated with a dramatic reduction of mature and progenitor cell populations, revealing a role in governing HSC lineage commitment. ChIP- and RNA-sequencing studies in HSC and progenitor cells revealed that Usp16 bound to many important hematopoietic regulators and that Usp16 deletion altered the expression of genes in transcription/chromosome organization, immune response, hematopoietic/lymphoid organ development, and myeloid/leukocyte differentiation. The altered gene expression was partly rescued by knockdown of PRC1 subunits, suggesting that Usp16 and PRC1 counterbalance each other to regulate cellular ubH2A level and gene expression in the hematopoietic system. We further discovered that knocking down Cdkn1a (p21cip1), a Usp16 target and regulated gene, rescued the altered cell cycle profile and differentiation defect of Usp16-deleted HSCs. Collectively, these studies identified Usp16 as one of the histone H2A deubiquitinases, which coordinates with the H2A ubiquitin ligase PRC1 to regulate hematopoiesis, and revealed cell cycle regulation by Usp16 as key for HSC differentiation.