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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Co-Repressor Proteins* / genetics
  • Co-Repressor Proteins* / metabolism
  • Epigenesis, Genetic*
  • Hematopoietic Stem Cells* / metabolism
  • Histone Deacetylases / metabolism
  • Humans

Substances

  • Co-Repressor Proteins
  • Histone Deacetylases

Grant support