UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex.
Cullin3 E3 ligase-mediated proteasomal degradation
HSC self-renewal
Kelch-BTB domain proteinUM171 small molecule
LSD1/RCOR1 CoREST complex
epigenetic modulation
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
21
07
2020
revised:
22
10
2020
accepted:
03
12
2020
entrez:
8
1
2021
pubmed:
9
1
2021
medline:
20
5
2021
Statut:
ppublish
Résumé
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. CRL3
Identifiants
pubmed: 33417871
pii: S1934-5909(20)30586-5
doi: 10.1016/j.stem.2020.12.002
pii:
doi:
Substances chimiques
Co-Repressor Proteins
0
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
48-62.e6Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Except for G.S., the authors declare no competing interests. G.S. is founder and CEO of ExCellThera, a small biotech that owns an exclusive license to UM171.