Loizou Joanna I, Oser Gabriela, Shukla Vivek, Sawan Carla, Murr Rabih, Wang Zhao-Qi, Trumpp Andreas, Herceg Zdenko
International Agency for Research on Cancer (IARC), Lyon, France.
J Immunol. 2009 Nov 15;183(10):6422-31. doi: 10.4049/jimmunol.0901969. Epub 2009 Oct 30.
The pool of hematopoietic stem/progenitor cells, which provide life-long reconstitution of all hematopoietic lineages, is tightly controlled and regulated by self-renewal and apoptosis. Histone modifiers and chromatin states are believed to govern establishment, maintenance, and propagation of distinct patterns of gene expression in stem cells, however the underlying mechanism remains poorly understood. In this study, we identified a role for the histone acetytransferase cofactor Trrap in the maintenance of hematopietic stem/progenitor cells. Conditional deletion of the Trrap gene in mice resulted in ablation of bone marrow and increased lethality. This was due to the depletion of early hematopoietic progenitors, including hematopoietic stem cells, via a cell-autonomous mechanism. Analysis of purified bone marrow progenitors revealed that these defects are associated with induction of p53-independent apoptosis and deregulation of Myc transcription factors. Together, this study has identified a critical role for Trrap in the mechanism that maintains hematopoietic stem cells and hematopoietic system, and underscores the importance of Trrap and histone modifications in tissue homeostasis.
造血干/祖细胞库能够终生重建所有造血谱系，其受到自我更新和细胞凋亡的严格控制与调节。组蛋白修饰因子和染色质状态被认为在干细胞中基因表达独特模式的建立、维持和传播中起主导作用，然而其潜在机制仍知之甚少。在本研究中，我们确定了组蛋白乙酰转移酶辅因子Trrap在维持造血干/祖细胞中的作用。小鼠中Trrap基因的条件性缺失导致骨髓消融和致死率增加。这是由于包括造血干细胞在内的早期造血祖细胞通过细胞自主机制耗竭所致。对纯化的骨髓祖细胞的分析表明，这些缺陷与p53非依赖性凋亡的诱导以及Myc转录因子的失调有关。总之，本研究确定了Trrap在维持造血干细胞和造血系统机制中的关键作用，并强调了Trrap和组蛋白修饰在组织稳态中的重要性。
