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

Chagraoui J, Girard S, Spinella JF, Simon L, Bonneil E, Mayotte N, MacRae T, Coulombe-Huntington J, Bertomeu T, Moison C, Tomellini E, Thibault P, Tyers M, Marinier A, Sauvageau G

Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada.

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.

Cell Stem Cell 2021;28(1):48-62.e6.

Pubmed ID: 33417871

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