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 Haney, Michael S. A1 Shankar, Archana A1 Hsu, Ian A1 Miyauchi, Masashi A1 Pálovics, Róbert A1 Khoo, Hwei Minn A1 Igarashi, Kyomi J. A1 Bhadury, Joydeep A1 Munson, Christy A1 Mack, Paul K. A1 Tan, Tze-Kai A1 Wyss-Coray, Tony A1 Nakauchi, Hiromitsu A1 Wilkinson, Adam C. 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.