Researchers at Duke University have shed light on mysterious “dark” stretches of the genome non-coding DNA whose function has long remained elusive revealing how these regions help cells sense and react to the mechanical properties of their surroundings.
Although only about 1-2 % of the human genome encodes proteins, the rest is thought to contain crucial regulatory sequences, such as enhancers, that fine-tune gene activity. By combining epigenetic profiling, sequencing, and CRISPR interference (CRISPRi), the team mapped DNA regions that respond to mechanical stimuli for example, how stiff or soft the tissue environment is and influence cellular behaviour. In laboratory experiments, cells were grown on hydrogels mimicking different stiffness levels. Within just 20 hours, thousands of genes changed expression, and nearly fifty thousand genomic regions shifted in accessibility. To test function, the researchers silenced candidate dark-genome regions and observed alterations in cell growth, movement, and gene regulation. Regions that affected cellular response specifically under mechanical variation were named mechanoenhancers.
Further analyses showed that mechanoenhancers physically interact with their target genes in a manner dependent on mechanical cues, and some of these regulatory elements are active in lung fibrosis patient samples, implicating them in disease. The authors suggest that mapping these mechanoenhancers across cell types, disease states, and aging may reveal new therapeutic targets especially for conditions where tissue mechanics change, like fibrosis, cancer, and degenerative disorders.
Image credit: Science (2025). DOI: 10.1126/science.adl1988 (Phys.org)
Article can be accessed on: Phys.org
