HomeLatest HappeningsLysine Acetyltransferase Tip60 Is Required for Hematopoietic Stem Cell Maintenance. (Blood, Jun 2020)
Lysine Acetyltransferase Tip60 Is Required for Hematopoietic Stem Cell Maintenance. (Blood, Jun 2020)
Akihiko Numata1, Hui Si Kwok1, Qi-Ling Zhou1, Jia Li1, Roberto Tirado-Magallanes2, Vladimir Espinosa Angarcia3, Rebecca Louise Hannah4, Jihye Park5, Chelsia Qiuxia Wang6, Vaidehi Krishnan3, Deepa Rajagopalan3, Yangzhou Zhang1, Siqin Zhou7, Robert Welner8, Motomi Osato2, Sudhakar Jha1, Stefan K Bohlander9, Bertie Göttgens10, Henry Yang3, Touati Benoukraf11, John W Lough12, Deepak Bararia1, Daniel G Tenen3
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.
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.