A transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 11 2023
09 11 2023
Historique:
received:
01
06
2023
accepted:
24
10
2023
medline:
13
11
2023
pubmed:
10
11
2023
entrez:
9
11
2023
Statut:
epublish
Résumé
Transcriptional mechanisms controlling developmental processes establish and maintain proteomic networks, which can govern the levels of intracellular small molecules. Although dynamic changes in bioactive small molecules can link transcription factor and genome activity with cell state transitions, many mechanistic questions are unresolved. Using quantitative lipidomics and multiomics, we discover that the hematopoietic transcription factor GATA1 establishes ceramide homeostasis during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Inhibiting a GATA1-induced sphingolipid biosynthetic enzyme, delta(4)-desaturase, or disrupting ceramide homeostasis with cell-permeable dihydroceramide or ceramide is detrimental to erythroid, but not myeloid, progenitor activity. Coupled with genetic editing-based rewiring of the regulatory circuitry, we demonstrate that ceramide homeostasis commissions vital stem cell factor and erythropoietin signaling by opposing an inhibitory protein phosphatase 2A-dependent, dual-component mechanism. Integrating bioactive lipids as essential components of GATA factor mechanisms to control cell state transitions has implications for diverse cell and tissue types.
Identifiants
pubmed: 37945603
doi: 10.1038/s41467-023-42978-w
pii: 10.1038/s41467-023-42978-w
pmc: PMC10636182
doi:
Substances chimiques
Cytokines
0
GATA1 Transcription Factor
0
Ceramides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
7262Subventions
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA097132
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM108538
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK050107
Pays : United States
Informations de copyright
© 2023. The Author(s).
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