Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
复制标题
机械敏感基因组增强剂增强细胞对基质刚度的反应。
DOI：
10.1101/2024.01.10.574997
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Gersbach,CharlesA
中科院分区：
文献类型：
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作者：
Cosgrove,BrianD;Bounds,LexiR;Taylor,CarsonKey;Su,AlanL;Rizzo,AnthonyJ;Barrera,Alejandro;Crawford,GregoryE;Hoffman,BrentonD;Gersbach,CharlesA
细胞转录和表型的表观遗传控制受到细胞微环境变化的影响，但来自这些微环境的机械线索如何精确地影响表观遗传状态以调节转录仍然在很大程度上未被映射。在这里，我们结合联合收割机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，以确定一类新的基因组增强子，响应机械微环境。这些“机械增强子”可以在软或硬的细胞外基质环境中起作用，并调节转录以影响关键的细胞功能，包括凋亡、机械转导、增殖和迁移。刚性材料上的机械增强子的表观遗传编辑将基因表达调整到较软材料上观察到的水平，从而重新编程细胞对机械微环境的反应。这些编辑方法可以精确改变机械驱动的疾病状态。
Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments 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 new class of genomic enhancers that responds to the mechanical microenvironment. These ‘mechanoenhancers’ could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.