TY - JOUR
T1 - Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance
AU - Numata, Akihiko
AU - Kwok, Hui Si
AU - Zhou, Qi Ling
AU - Li, Jia
AU - Tirado-Magallanes, Roberto
AU - Angarica, Vladimir Espinosa
AU - Hannah, Rebecca
AU - Park, Jihye
AU - Wang, Chelsia Qiuxia
AU - Krishnan, Vaidehi
AU - Rajagopalan, Deepa
AU - Zhang, Yanzhou
AU - Zhou, Siqin
AU - Welner, Robert S.
AU - Osato, Motomi
AU - Jha, Sudhakar
AU - Bohlander, Stefan K.
AU - Göttgens, Berthold
AU - Yang, Henry
AU - Benoukraf, Touati
AU - Lough, John W.
AU - Bararia, Deepak
AU - Tenen, Daniel G.
N1 - Funding Information:
This work was supported by the National Research Foundation, Singapore; the Singapore Ministry of Education; a Singapore Translational Research Award from the Singapore National Medical Research Council (NMRC/STaR/ 00018/2013) (D.G.T.); National Institutes of Health, National Cancer Institute grant R35CA197697 and National Heart, Lung and Blood Institute grant and P01HL131477 (D.G.T.); Cancer Research UK grant C1163/A21762 and Wellcome Trust grant 206328/Z/17/Z (B.G.). a research fellowship from the Uehara Memorial Foundation (A.N.), and funds from the Leukaemia and Blood Cancer New Zealand and the family of Marijana Kumerich (S.K.B.).
Funding Information:
The authors thank Bruno Amati (Italian Institute of Technology, Milan, Italy) for providing rabbit polyclonal Tip60 antibodies; Issay Kitabayshi (National Cancer Research Center, Tokyo, Japan) and Chunaram Choudhary (The Novo Nordisk Foundation Center for Protein Research, Copenhagen, Denmark) for helpful discussions; Celestina Chin Ai Qi (CSI Singapore) for proofreading the manuscript; Cai Ping Koh (CSI Singapore) and members of the Tenen laboratory for technical support and helpful discussions; and the FACS facility and Quantitative Proteomics Core (CSI Singapore), Beijing Genomics Institute (Hong Kong, China), and Duke-NUS Genome Biology Facility (Singapore) for technical support. This work was supported by the National Research Foundation, Singapore; the Singapore Ministry of Education; a Singapore Translational Research Award from the Singapore National Medical Research Council (NMRC/STaR/ 00018/2013) (D.G.T.); National Institutes of Health, National Cancer Institute grant R35CA197697 and National Heart, Lung and Blood Institute grant and P01HL131477 (D.G.T.); Cancer Research UK grant C1163/A21762 and Wellcome Trust grant 206328/Z/17/Z (B.G.). a research fellowship from the Uehara Memorial Foundation (A.N.), and funds from the Leukaemia and Blood Cancer New Zealand and the family of Marijana Kumerich (S.K.B.).
Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/10/8
Y1 - 2020/10/8
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019001279
DO - 10.1182/blood.2019001279
M3 - Article
C2 - 32542325
AN - SCOPUS:85092749723
SN - 0006-4971
VL - 136
SP - 1735
EP - 1747
JO - Blood
JF - Blood
IS - 15
ER -