Identification of the Saga Complex As a Key Regulator of Hematopoiesis

The hematopoietic system declines with age, and its dysfunction is associated with many diseases, ranging from infections to cancers. However, the processes that sustain lifelong hematopoiesis remain incompletely understood. To identify genetic regulators of hematopoiesis, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform. Targeting ~2000 genes with this platform, we identified SAGA complex members Tada2b and Taf5l as key regulators of hematopoiesis. Genetic perturbation of Tada2b or Taf5l in murine HSCs led to significant HSC expansion ex vivo, strongly inhibited hematopoiesis in vivo, led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. These results were validated in an ex vivo human HSC culture as well, and loss of these SAGA complex components enhanced the cell outgrowth and drives interferon pathway gene expression in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression in humans. Altogether, this study offers a new platform to screen genetic regulators of hematopoiesis and identifies novel regulators of hematopoiesis.

Nakauchi:Megakaryon: Consultancy, Current equity holder in private company; Century Therapeutics: Consultancy, Current equity holder in publicly-traded company; ReproCELL: Consultancy, Current equity holder in private company. Wilkinson:ImmuneBRIDGE: Consultancy.