Mechano-epigenetic enhancement of CRISPR activation of target genes for cell reprogramming [ATAC-Seq CO]

ABSTRACT: Mechanical cues can reshape chromatin organization, yet whether such changes at specific loci can be harnessed to activate gene expression remains unclear. Here, we show that transient nuclear deformation not only drives global remodeling of chromatin accessibility, DNA methylation, and higher-order genome architecture but also reproducibly increasing accessibility at promoters of transcription factors, including Ascl1 and Oct4. By coupling CRISPR-based transcriptional activation (CRISPRa) with guide RNAs designed to target these mechanically primed regions, we achieve enhanced activation of endogenous genes and improved fibroblast-to-neuron reprogramming efficiency. In addition, mechanically informed CRISPR activation of endogenous Oct4 induces a transient partial reprogramming state that further boosts reprogramming outcomes. Together, these findings establish a mechano-epigenetic strategy for overcoming chromatin barriers and provide a general framework for improving cell fate conversion.

ORGANISM(S): Mus musculus

PROVIDER: GSE347813 | GEO | 2026/09/22

REPOSITORIES: GEO