RT Journal Article
SR Electronic
T1 Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.22.501030
DO 10.1101/2022.07.22.501030
A1 Michael S. Haney
A1 Archana Shankar
A1 Ian Hsu
A1 Masashi Miyauchi
A1 Róbert Pálovics
A1 Hwei Minn Khoo
A1 Kyomi J. Igarashi
A1 Joydeep Bhadury
A1 Christy Munson
A1 Paul K. Mack
A1 Tze-Kai Tan
A1 Tony Wyss-Coray
A1 Hiromitsu Nakauchi
A1 Adam C. Wilkinson
YR 2022
UL http://biorxiv.org/content/early/2022/07/22/2022.07.22.501030.abstract
AB The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To address this knowledge gap, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform to enable the genetic interrogation of hematopoiesis and broad aspects of immune cell function in vivo. Targeting ∼7000 genes with this methodology, we discovered SAGA complex members Tada2b and Taf5l as key regulators of HSC lineage commitment. Loss of Tada2b or Taf5l inhibited hematopoiesis in vivo and was associated with upregulation of interferon response gene expression. SAGA complex member expression is significantly reduced in aged HSCs and upregulated with heterochronic parabiosis, suggesting a novel mechanism of age-associated hematopoietic decline and rejuvenation. Our study provides a rich functional genetics resource of hematopoiesis regulators accessible through a public interactive database (www.hematopoiesiscrisprscreens.com), a novel mechanism regulating age-related decline of hematopoiesis, and a new methodology with broad applications to systematically probe the development and functions of the lymphohematopoietic system.Competing Interest StatementH.N. is a co-founder and shareholder in ReproCELL, Megakaryon, and Century Therapeutics.