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    Area of Science:

    • Genomics
    • Epigenetics
    • Cellular senescence

    Background:

    • Enhancers regulate gene expression context-specifically, often at distant genomic locations.
    • Cellular senescence involves significant three-dimensional (3D) genome reorganization, but enhancer reconfiguration dynamics remain poorly understood.
    • Understanding enhancer interactomes is crucial for deciphering gene regulation in aging and disease.

    Approach:

    • Generated high-resolution contact maps of active enhancers and target genes.
    • Assessed chromatin accessibility, histone modifications, and transcription factor binding.
    • Performed motif analysis to identify key regulatory transcription factors.

    Key Points:

    • Hyper-connected enhancer communities form around highly expressed genes in essential pathways during senescence.
    • The transcription factor MafK is upregulated in senescence and its reduction alleviates senescence phenotypes.
    • Aging in mouse liver shows similar hyper-connected enhancer communities regulating cell differentiation and homeostasis genes.

    Conclusions:

    • Hyper-connected enhancer communities correlate with elevated gene expression in senescence and aging.
    • These enhancer connectomes represent potential therapeutic targets for aging and associated diseases.