PT  - JOURNAL ARTICLE
AU  - Michael S. Haney
AU  - Archana Shankar
AU  - Ian Hsu
AU  - Masashi Miyauchi
AU  - Róbert Pálovics
AU  - Hwei Minn Khoo
AU  - Kyomi J. Igarashi
AU  - Joydeep Bhadury
AU  - Christy Munson
AU  - Paul K. Mack
AU  - Tze-Kai Tan
AU  - Tony Wyss-Coray
AU  - Hiromitsu Nakauchi
AU  - Adam C. Wilkinson
TI  - Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging
AID  - 10.1101/2022.07.22.501030
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.22.501030
4099  - http://biorxiv.org/content/early/2022/07/22/2022.07.22.501030.short
4100  - http://biorxiv.org/content/early/2022/07/22/2022.07.22.501030.full
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.