UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex

  • Cell Stem Cell. 2021 Jan 7;28(1):48-62.e6. doi: 10.1016/j.stem.2020.12.002.
Jalila Chagraoui  1 ,  Simon Girard  1 ,  Jean-Francois Spinella  1 ,  Laura Simon  1 ,  Eric Bonneil  2 ,  Nadine Mayotte  1 ,  Tara MacRae  1 ,  Jasmin Coulombe-Huntington  3 ,  Thierry Bertomeu  3 ,  Celine Moison  1 ,  Elisa Tomellini  1 ,  Pierre Thibault  2 ,  Mike Tyers  3 ,  Anne Marinier  4 ,  Guy Sauvageau  5
Affiliations
  • 1. Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada.
  • 2. Departments of Biochemistry and Chemistry, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada.
  • 3. Department of Medicine, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada.
  • 4. Faculty of Arts and Science, Université de Montréal, Montreal, QC, Canada.
  • 5. Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. Electronic address: [email protected].
PMID: 33417871 DOI: 10.1016/j.stem.2020.12.002
Abstract

Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacity when cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, most notably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylase LSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulates the CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activity of UM171. The mechanism underlying the UM171-mediated loss of CoREST function remains undetermined. We now report that UM171 potentiates the activity of a CULLIN3-E3 ubiquitin Ligase (CRL3) complex whose target specificity is dictated by the poorly characterized Kelch/BTB domain protein KBTBD4. CRL3KBTBD4 targets components of the LSD1/RCOR1 corepressor complex for proteasomal degradation, hence re-establishing H3K4me2 and H3K27ac epigenetic marks, which are rapidly decreased upon ex vivo culture of human HSCs.

Keywords
Cullin3 E3 ligase-mediated proteasomal degradation; HSC self-renewal; Kelch-BTB domain proteinUM171 small molecule; LSD1/RCOR1 CoREST complex; epigenetic modulation.