Histone acetyltransferase cofactor Trrap is essential for maintaining the hematopoietic stem/progenitor cell pool.
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.
Loizou
Joanna I
JI
International Agency for Research on Cancer (IARC), Lyon, France.
Oser
Gabriela
G
Shukla
Vivek
V
Sawan
Carla
C
Murr
Rabih
R
Wang
Zhao-Qi
ZQ
Trumpp
Andreas
A
Herceg
Zdenko
Z
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D003067:Coenzymes / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003067:Coenzymes; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C113829:transformation-transcription domain-associated protein; D051548:Histone Acetyltransferases