Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance.
Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance.
复制标题
DOI：
10.1038/cdd.2015.140
复制
发表时间：
2016-05
影响因子：
12.4
通讯作者：
Nijnik A
中科院分区：
文献类型：
--
作者：
Belle JI;Petrov JC;Langlais D;Robert F;Cencic R;Shen S;Pelletier J;Gros P;Nijnik A
p53是细胞应激反应的中心介质，其精确调节对于造血的正常进展是必不可少的。MYSM 1是维持造血干细胞（HSC）功能、造血祖细胞存活和淋巴细胞发育所必需的表观遗传调节因子。我们最近证明，Mysm 1缺陷的所有发育和造血表型都是p53介导的，并在Mysm 1 −/−p53−/−小鼠模型中得到了拯救。然而，触发Mysm 1 −/− HSPC中p53激活的机制以及p53下游驱动Mysm 1 −/−表型不同方面的途径仍然未知。在这里，我们展示了Mysm 1 −/− HSPCs中p53应激反应的转录激活。从机制上讲，我们发现MYSM 1蛋白与p53相关，并与经典的p53靶基因Bbc 3/p53 A（p53上调的凋亡调节因子）和Cdkn 1a/p21的启动子共定位。此外，它通过调节局部组蛋白修饰（H3 K27 ac和H3 K4 me 3）和p53募集来拮抗它们的p53驱动的表达。使用双基因敲除小鼠模型，我们确定了p53驱动的Mysm 1 −/−造血功能障碍的重要介导因子是CD 40 A，而不是p21。具体而言，Mysm 1 −/−Puma−/−小鼠表现出多能祖细胞（MPP）活力的完全拯救，HSC静止和功能的部分拯救，但持续的淋巴细胞减少症。通过Mysm 1 −/−Puma−/− MPPs的转录组分析，我们证明了其他p53诱导的凋亡和细胞周期停滞介质的强烈上调。Mysm 1 −/−Puma−/− MPP的完全活力，尽管许多其他促凋亡介质的强烈上调，确立了Mysm 1 −/−Puma−/− MPP作为p53诱导的MPP凋亡的重要非冗余效应子。此外，我们确定了p53依赖性但PUMA非依赖性Mysm 1 −/−造血缺陷表型的潜在介质。总体而言，我们的研究提供了新的见解细胞类型特异性的作用，p53及其下游效应在造血使用独特的模型p53过度活跃内源性应激诱导。我们的结论是，MYSM 1是一个关键的负调控p53转录程序在造血，它的抑制Bbc 3/cDNAA的表达是必不可少的MPP生存，并部分有助于维持HSC功能。
p53 is a central mediator of cellular stress responses, and its precise regulation is essential for the normal progression of hematopoiesis. MYSM1 is an epigenetic regulator essential for the maintenance of hematopoietic stem cell (HSC) function, hematopoietic progenitor survival, and lymphocyte development. We recently demonstrated that all developmental and hematopoietic phenotypes of Mysm1 deficiency are p53-mediated and rescued in the Mysm1−/−p53−/− mouse model. However, the mechanisms triggering p53 activation in Mysm1−/− HSPCs, and the pathways downstream of p53 driving different aspects of the Mysm1−/− phenotype remain unknown. Here we show the transcriptional activation of p53 stress responses in Mysm1−/− HSPCs. Mechanistically, we find that the MYSM1 protein associates with p53 and colocalizes to promoters of classical p53-target genes Bbc3/PUMA (p53 upregulated modulator of apoptosis) and Cdkn1a/p21. Furthermore, it antagonizes their p53-driven expression by modulating local histone modifications (H3K27ac and H3K4me3) and p53 recruitment. Using double-knockout mouse models, we establish that PUMA, but not p21, is an important mediator of p53-driven Mysm1−/− hematopoietic dysfunction. Specifically, Mysm1−/−Puma−/− mice show full rescue of multipotent progenitor (MPP) viability, partial rescue of HSC quiescence and function, but persistent lymphopenia. Through transcriptome analysis of Mysm1−/−Puma−/− MPPs, we demonstrate strong upregulation of other p53-induced mediators of apoptosis and cell-cycle arrest. The full viability of Mysm1−/−Puma−/− MPPs, despite strong upregulation of many other pro-apoptotic mediators, establishes PUMA as the essential non-redundant effector of p53-induced MPP apoptosis. Furthermore, we identify potential mediators of p53-dependent but PUMA-independent Mysm1−/−hematopoietic deficiency phenotypes. Overall, our study provides novel insight into the cell-type-specific roles of p53 and its downstream effectors in hematopoiesis using unique models of p53 hyperactivity induced by endogenous stress. We conclude that MYSM1 is a critical negative regulator of p53 transcriptional programs in hematopoiesis, and that its repression of Bbc3/PUMA expression is essential for MPP survival, and partly contributes to maintaining HSC function.