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Histone Acetyltransferase Cofactor Trrap Is Essential for Maintaining the Hematopoietic Stem/Progenitor Cell Pool¹

Joanna I. Loizou,^* Gabriela Oser, Vivek Shukla,^* Carla Sawan,^* Rabih Murr,^*¶ Zhao-Qi Wang,^|| Andreas Trumpp,^# and Zdenko Herceg^2*

^*International Agency for Research on Cancer (IARC), Lyon, France; Mammalian Genetics Laboratory, Cancer Research U.K., London Research Institute, Lincoln’s Inn Fields Laboratories, London, U.K.; Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Mammalian Department of Biochemistry, Beadle Center, Lincoln, NE 68588; ^¶Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; ^||Leibniz Institut for Age Research Fritz Lipmann Institut, Jena, Germany; and ^#Deutsches Krebsforschungszentrum (DKFZ) Im Neuenheimer Feld 280, Heidelberg, Germany

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.I.L., G.O., V.S., C.S., and R.M. performed all the experiments. Z.H. and J.I.L. coordinated the project and wrote the manuscript. Z.Q.W. and A.T. gave conceptual assistance and contributed with planning the experiments. All authors discussed the results and manuscript text.

² Address correspondence and reprint requests to Dr. Zdenko Herceg, Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, Lyon, France. E-mail address: herceg{at}iarc.fr

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; HAT, histone acetyltransferase; TRRAP, TRansformation/tRanscription domain-Associated Protein; PCAF, p300/CBP-associated factor complex; pIpC, poly(inosinic)-poly(cytidylic) acid; WT, wild type; BM, bone marrow; CKO, conditional knockout; FISH, fluorescence in situ hybridization.

⁴ The online version of this article contains supplementary material.