Lysine Acetyltransferase Tip60 Is Required for Hematopoietic Stem Cell Maintenance. (Blood, Jun 2020)

Akihiko Numata 1Hui Si Kwok 1Qi-Ling Zhou 1Jia Li 1Roberto Tirado-Magallanes 2Vladimir Espinosa Angarcia 3Rebecca Louise Hannah 4Jihye Park 5Chelsia Qiuxia Wang 6Vaidehi Krishnan 3Deepa Rajagopalan 3Yangzhou Zhang 1Siqin Zhou 7Robert Welner 8Motomi Osato 2Sudhakar Jha 1Stefan K Bohlander 9Bertie Göttgens 10Henry Yang 3Touati Benoukraf 11John W Lough 12Deepak Bararia 1Daniel G Tenen 3

Author Information

1Cancer Science Institute of Singapore, Singapore, Singapore.
2National University of Singapore, Singapore, Singapore.
3Cancer Science Institute of Singapore, Singapore, Singapore.
4University of Cambridge, Cambridge, United Kingdom.
5Dicerna Pharmaceuticals, Cambridge, Massachusetts, United States.
6Cancer Science Institute of Singapore, NUS, Singapore, Singapore.
7Cancer Science Institute of Singapore, National University of Singapore, Singapore.
8University of Alabama at Birmingham, Birmingham, Alabama, United States.
9University of Auckland, Auckland, New Zealand.
10Cambridge University, Cambridge, United Kingdom.
11Memorial University of Newfoundland, St. John’s, Canada.
12Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

Abstract:

Hematopoietic stem cells (HSC) have the potential to replenish the blood system for the lifetime of the organism. Their two defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Here, using conditional gene knockout models, we demonstrate a critical requirement of lysine acetyltransferase 5 (Kat5, also known as Tip60) for murine HSC maintenance both in 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 co-localizes 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-cycle 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.

Copyright © 2020 American Society of Hematology.

PMID: 32542325 DOI: 10.1182/blood.2019001279