2. Academic Validation
  3. Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

  • Science. 2025 Sep 25:eadl1988. doi: 10.1126/science.adl1988.
Brian D Cosgrove # 1 2,  Lexi R Bounds # 1 2,  Carson Key Taylor # 1 2,  Alan L Su 1 2,  Anthony J Rizzo 1 2,  Alejandro Barrera 2 3,  Tongyu Sun 4,  Alexias Safi 2 5,  Lingyun Song 2 5,  Thomas Whitlow 4,  Aleksandra Tata 4 6,  Nahid Iglesias 1 2,  Yarui Diao 2 4 7,  Purushothama Rao Tata 2 4 7 8,  Brenton D Hoffman 1 4,  Gregory E Crawford 2 5,  Charles A Gersbach 1 2 4 6 7
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Duke University, Durham, NC, USA.
  • 2 Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
  • 3 Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
  • 4 Department of Cell Biology, Duke University, Durham, NC, USA.
  • 5 Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
  • 6 Department of Surgery, Duke University Medical Center, Durham, NC, USA.
  • 7 Duke Regeneration Center, Duke University, Durham, NC, USA.
  • 8 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
  • # Contributed equally.
PMID: 40997217 DOI: 10.1126/science.adl1988
Abstract

Epigenetic control of gene expression and cellular phenotype is influenced by changes in the local microenvironment, yet how mechanical cues precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a class of genomic enhancers that responds to the mechanical microenvironment. These "mechanoenhancers" can be preferentially activated on either soft or stiff extracellular matrix contexts and regulate transcription to influence critical cell functions including Apoptosis, adhesion, proliferation, and migration. Epigenetic editing of mechanoenhancers reprograms the cellular response to the mechanical microenvironment and modulates the activation of disease-related genes in lung fibroblasts from healthy and fibrotic donors. Epigenetic editing of mechanoenhancers holds potential for precise targeting of mechanically-driven diseases.

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