Researchers at Karolinska Institute performed integrated ATAC-seq and mRNA-seq in daf-2 and wild-type C. elegans to map chromatin accessibility changes with age and under reduced insulin/IGF signaling. They discovered that enhancer regions closing during normal aging are reopened in daf-2 mutants by the homeobox transcription factor LIN-39, which acts in collaboration with DAF-16/FOXO within developing VC motor neurons. Stage-specific RNAi localized LIN-39’s role to L3-stage neuron maturation, establishing it as a developmental determinant of longevity.

Key points

• Integrated ATAC-seq and mRNA-seq in daf-2(e1370) and glp-4(bn2) C. elegans identify enhancer regions reopening under reduced IIS that close during normal aging.
• Neuron-specific and L3-stage RNAi of LIN-39 abolishes lifespan extension in daf-2 mutants, pinpointing its role in VC motor neuron maturation.
• LIN-39 and DAF-16/FOXO co-open enhancer regions to activate transcriptional programs counteracting epigenetic aging, extending C. elegans lifespan.

Why it matters: Discovery of a developmental transcriptional mechanism that reopens aging-silenced enhancers offers a novel approach to modulate lifespan through epigenetic therapy.