Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance. (Blood, Oct 2020)

/ 2020, Latest Happenings, Research / By

Akihiko Numata 1 2, Hui Si Kwok 1, Qi-Ling Zhou 1, Jia Li 1, Roberto Tirado-Magallanes 1, Vladimir Espinosa Angarica 1, Rebecca Hannah 3 4, Jihye Park 5, Chelsia Qiuxia Wang 1, Vaidehi Krishnan 1, Deepa Rajagopalan 1, Yanzhou Zhang 1, Siqin Zhou 1, Robert S Welner 6, Motomi Osato 1, Sudhakar Jha 1, Stefan K Bohlander 7, Berthold Göttgens 3 4, Henry Yang 1, Touati Benoukraf 1 8, John W Lough 9, Deepak Bararia 1 10, Daniel G Tenen 1 10

Author Information

1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
3Department of Haematology, Wellcome and Medical Research Council Cambridge Stem Cell Institute, and.
4Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
5Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA.
6Hematology Oncology, Department of Medicine, The University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
7Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
8Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John’s, NL, Canada.
9Department of Cell Biology, Neurobiology, and Anatomy, and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI; and.
10Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.

Abstract:

Hematopoietic stem cells (HSCs) have the potential to replenish the blood system for the lifetime of the organism. Their 2 defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Using conditional gene-knockout models, we demonstrated a critical requirement of lysine acetyltransferase 5 (Kat5, also known as Tip60) for murine HSC maintenance in both the embryonic and adult stages, which depends on its acetyltransferase activity. Genome-wide chromatin and transcriptome profiling in murine hematopoietic stem and progenitor cells revealed that Tip60 colocalizes with c-Myc and that Tip60 deletion suppress the expression of Myc target genes, which are associated with critical biological processes for HSC maintenance, cell cycling, and DNA repair. Notably, acetylated H2A.Z (acH2A.Z) was enriched at the Tip60-bound active chromatin, and Tip60 deletion induced a robust reduction in the acH2A.Z/H2A.Z ratio. These results uncover a critical epigenetic regulatory layer for HSC maintenance, at least in part through Tip60-dependent H2A.Z acetylation to activate Myc target genes.

© 2020 by The American Society of Hematology.

 

PMID: 32542325 DOI: 10.1182/blood.2019001279

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