HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
04
01
2022
accepted:
08
09
2022
revised:
07
09
2022
pubmed:
29
9
2022
medline:
2
11
2022
entrez:
28
9
2022
Statut:
ppublish
Résumé
Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.
Identifiants
pubmed: 36171271
doi: 10.1038/s41388-022-02471-y
pii: 10.1038/s41388-022-02471-y
pmc: PMC7613766
mid: EMS154002
doi:
Substances chimiques
Chromatin
0
DNA-Binding Proteins
0
GFI1 protein, human
0
Histone Demethylases
EC 1.14.11.-
Transcription Factors
0
HMG20B protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4841-4854Subventions
Organisme : Cancer Research UK
ID : A27412
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A19280
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5759/A20971
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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