biostudies-literatureShankar AEuropean Hematology Association (EHA)Kay Kendall Leukaemia FundLeukemia and Lymphoma Society (Leukemia & Lymphoma Society)European Hematology AssociationKay Kendall Leukaemia Fund (KKLF)U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteWellcome TrustU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)Leukemia and Lymphoma Society1756https://www.ebi.ac.uk/biostudies/studies/S-EPMC12914052biostudies-literatureUnknown17(1)The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for cell intrinsic regulators of hematopoiesis, we perform a genome-wide in vivo hematopoietic stem and progenitor cell (HSPC)-based CRISPR knockout screen. We discover SAGA complex members, including Tada2b and Taf5l, as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibits hematopoiesis in vivo, causing a buildup of immature hematopoietic cells in the bone marrow. The SAGA complex deposits histone H3 lysine 9 acetylation (H3K9ac) and removes histone H2B ubiquitination (H2Bub). Loss of Tada2b leads to a reduction in H3K9ac levels and altered H2Bub enrichment in HSPCs, implicating disruption of SAGA complex activity. This is associated wiNature communicationsIn vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.PMC12914052203151/A/16/Z302479/Z/23/ZK99HL1502183385-19KKL1378302479Z23ZRG-202211-02958Igarashi KJMeaker GAIwama AOlender LPalovics RWyss-Coray THaney MSWilkinson ACKhoo HMRizq ONakauchi HMack PKShankar AKaito STan TKBozhilov YBhadury JMiyauchi MMunson CHsu IRehwinkel JfalseIn vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for cell intrinsic regulators of hematopoiesis, we perform a genome-wide in vivo hematopoietic stem and progenitor cell (HSPC)-based CRISPR knockout screen. We discover SAGA complex members, including Tada2b and Taf5l, as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibits hematopoiesis in vivo, causing a buildup of immature hematopoietic cells in the bone marrow. The SAGA complex deposits histone H3 lysine 9 acetylation (H3K9ac) and removes histone H2B ubiquitination (H2Bub). Loss of Tada2b leads to a reduction in H3K9ac levels and altered H2Bub enrichment in HSPCs, implicating disruption of SAGA complex activity. This is associated wi2026-01-01T00:00:00Z2026 Jan2026-07-16T06:56:45.392Z2026-07-09T13:10:47.232ZS-EPMC129140524157769310.1038/s41467-026-68465-6