Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan.
Animals
Animals, Genetically Modified
Blood Glucose
/ metabolism
Caenorhabditis elegans
/ drug effects
Caenorhabditis elegans Proteins
/ genetics
Class II Phosphatidylinositol 3-Kinases
/ genetics
Diabetes Mellitus, Type 2
/ genetics
Gene Expression Regulation
Humans
Insulin
/ metabolism
Insulin Resistance
Insulin-Like Growth Factor I
/ genetics
Longevity
/ drug effects
Methylation
Mice
Papaverine
/ pharmacology
Repressor Proteins
/ genetics
Signal Transduction
Transcription Factors
/ genetics
Vorinostat
/ pharmacology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 01 2022
10 01 2022
Historique:
received:
25
05
2021
accepted:
06
12
2021
entrez:
11
1
2022
pubmed:
12
1
2022
medline:
27
1
2022
Statut:
epublish
Résumé
Aging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.
Identifiants
pubmed: 35013237
doi: 10.1038/s41467-021-27732-4
pii: 10.1038/s41467-021-27732-4
pmc: PMC8748497
doi:
Substances chimiques
Blood Glucose
0
Caenorhabditis elegans Proteins
0
GRH-1 protein, C elegans
0
GRHL1 protein, human
0
Grhl1 protein, mouse
0
IGF1 protein, human
0
Insulin
0
Repressor Proteins
0
Transcription Factors
0
Vorinostat
58IFB293JI
Insulin-Like Growth Factor I
67763-96-6
Papaverine
DAA13NKG2Q
Class II Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107Subventions
Organisme : NIH HHS
ID : P40 OD010440
Pays : United States
Informations de copyright
© 2022. The Author(s).
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