Intermittent Fasting Reprograms Chromatin Accessibility to Modulate Gene Expression in Brain and Muscle

Intermittent fasting (IF), a dietary regimen that mimics the natural feeding patterns observed across diverse organisms—from single-celled life to mammals—is thought to activate systemic survival responses and confer health benefits. However, the molecular mechanisms underlying these effects remain poorly understood. In this study, we utilized ATAC-Seq and RNA-Seq to investigate how IF influences chromatin accessibility and gene expression in brain and muscle tissues of mice, compared to ad libitum feeding. Our results reveal that IF induces significant changes in chromatin accessibility, modulating pathways related to metabolism, ribosome function, HIF-1 signaling, and glycolysis. Motif analysis identified tissue-specific transcription factors enriched in IF-regulated regions, including Sp1, Mef2a, NeuroD2, Banp, and NFIA in the brain, and SMAD4, TCF4, STAT5B, NKX3-1, and ZEB2 in muscle. Integrative analysis of ATAC-Seq and RNA-Seq data demonstrated that IF upregulates 50 genes and downregulates 15 in the cortex, while upregulating 31 genes and downregulating 10 in muscle. These gene expression changes are linked to pathways associated with neuroprotection and enhanced muscle function, offering mechanistic insights into the health benefits of IF. Our findings underscore the role of IF-induced chromatin remodeling in driving adaptive gene regulation.