In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis
Year: 2026
Type: article
Abstract: 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 with upregulation of interferon pathway genes, reduced mitochondrial activity, and increased megakaryocyte progenitor cell commitment. Loss of these factors also enhances the cell outgrowth and the interferon pathway in an in vivo human myelodysplastic syndrome cell line model. In summary, this study identifies the SAGA complex as an important regulator of hematopoiesis.
Source: Nature Communications
Authors: Archana Shankar, Leonid Olender, Ian Hsu, Masashi Miyauchi, Róbert Pálovics, Grace A. Meaker, Satoshi Kaito, Ola Rizq, Hwei Minn Khoo, Yavor Bozhilov, Kyomi J. Igarashi, Joydeep Bhadury, Christy Munson, Paul K. Mack, Tze-Kai Tan, Jan Rehwinkel, Atushi Iwama, Tony Wyss-Coray, Hiromitsu Nakauchi, Michael S. Haney, Adam C. Wilkinson
Institutions: Stanford Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Institute of Medical Science, The University of Tokyo, University of Gothenburg, Institute of Integrated Research, Institute of Science Tokyo, University of Pennsylvania
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Leukemia and Lymphoma Society, European Hematology Association, Wellcome Trust, Buck Institute for Research on Aging, Kay Kendall Leukaemia Fund, Vetenskapsrådet, National Institutes of Health, Institute of Medical Science, University of Tokyo, National Institute on Aging, National Heart, Lung, and Blood Institute
Awards: A synthetic hematopoietic stem cell niche to investigate stemness and hematopathologies, Cambridge Stem Cell Institute, G2633058902, G3105680844, G3629390256, G4149609790, Determining haematopoietic stem cell activity for biomedical discovery, G5570888479, Modulating HSC-niche interactions to understand aging and improve transplantation, G73635186, Cambridge Stem Cell Institute, Determining haematopoietic stem cell activity for biomedical discovery, G9000028324, G9000171483, Molecular signature of parabiosis, Training in Basic Research on Aging and Age-Related Disease, Cambridge Stem Cell Institute
OpenAlex ID: W7125521556