biostudies-literatureLim CYMinistry of Science and Technology, TaiwanNIA NIH HHSNIH HHSNational Institute on Aging224-240https://www.ebi.ac.uk/biostudies/studies/S-EPMC9809948biostudies-literatureUnknown19(1)Dietary restriction (DR) is known to promote autophagy to exert its longevity effect. While SAMS-1 (S-adenosyl methionine synthetase-1) has been shown to be a key mediator of the DR response, little is known about the roles of S-adenosyl methionine (SAM) and SAM-dependent methyltransferase in autophagy and DR-induced longevity. In this study, we show that DR and SAMS-1 repress the activity of SET-2, a histone H3K4 methyltransferase, by limiting the availability of SAM. Consequently, the reduced H3K4me3 levels promote the expression and activity of two transcription factors, HLH-30/TFEB and PHA-4/FOXA, which both regulate the transcription of autophagy-related genes. We then find that HLH-30/TFEB and PHA-4/FOXA act collaboratively on their common target genes to mediate the transcriptional AutophagySAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity.PMC9809948R01 AG072791MOST 109-2628-B010-012R21 AG058038MOST 110-2311-B-A49A-502P40 OD010440AG058038R01 AG028664AG028664R01 AG038664Lin HTWang FYLu TCChing TTKang YHHsu ALLim CYKumsta CHansen MfalseSAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity.Dietary restriction (DR) is known to promote autophagy to exert its longevity effect. While SAMS-1 (S-adenosyl methionine synthetase-1) has been shown to be a key mediator of the DR response, little is known about the roles of S-adenosyl methionine (SAM) and SAM-dependent methyltransferase in autophagy and DR-induced longevity. In this study, we show that DR and SAMS-1 repress the activity of SET-2, a histone H3K4 methyltransferase, by limiting the availability of SAM. Consequently, the reduced H3K4me3 levels promote the expression and activity of two transcription factors, HLH-30/TFEB and PHA-4/FOXA, which both regulate the transcription of autophagy-related genes. We then find that HLH-30/TFEB and PHA-4/FOXA act collaboratively on their common target genes to mediate the transcriptional 2023-01-01T00:00:00Z2023 Jan2025-05-29T16:22:08.433Z2025-05-29T16:22:08.433ZS-EPMC98099483550343510.1080/15548627.2022.2068267