课题组研究人员结合全基因组表观基因组分析、表观基因组编辑、表型和单细胞RNA-seq CRISPR筛选来鉴定一类对机械微环境有反应的基因组增强子。这些“机械增强子”可以在软或硬的细胞外基质环境下优先激活，并调节转录以影响关键的细胞功能，包括凋亡、粘附、增殖和迁移。机械增强子的表观遗传编辑重新编程细胞对机械微环境的反应，并调节来自健康和纤维化供体的肺成纤维细胞中疾病相关基因的激活。机械增强子的表观遗传编辑具有精确靶向机械驱动疾病的潜力。
据悉，基因表达和细胞表型的表观遗传控制受到局部微环境变化的影响，但机械线索如何精确影响表观遗传状态以调节转录仍未明确。
附：英文原文
Title: Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness
Author: Brian D. Cosgrove, Lexi R. Bounds, Carson Key Taylor, Alan L. Su, Anthony J. Rizzo, Alejandro Barrera, Tongyu Sun, Alexias Safi, Lingyun Song, Thomas Whitlow, Aleksandra Tata, Nahid Iglesias, Yarui Diao, Purushothama Rao Tata, Brenton D. Hoffman, Gregory E. Crawford, Charles A. Gersbach
Issue&Volume: 2025-09-25
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.
DOI: adl1988
Source: https://www.science.org/doi/10.1126/science.adl1988