Amazing stuff!
"Researchers ... used CRISPR technologies to discover previously unannotated stretches of DNA in the "dark genome" that are responsible for controlling how cells sense and respond to the mechanical properties of their local environment. ..."
"Only 1-2% of our genome encodes for genes. The other 98% of the genome clearly plays an important role in shaping cell identity, response to the environment, and susceptibility to disease, but until recently we didn’t have the tools to probe the function of this ‘dark’ part of our genome,” ...
they made hydrogels that mimic tissues of different stiffness and cultured cells on these gels. The researchers then used sequencing tools to quantify RNA levels and map regions of open chromatin, or accessible DNA, in order to determine changes to gene expression and genome structure in each sample.
“In just 20 hours on the different gels, we observed changes in the levels of thousands of genes and the structure of almost fifty thousand regions of the genome,” ... “This underscores the profound effect of the mechanical microenvironment on cell biology and clarifies how changes in tissue structure can play a significant role in diseases like fibrosis and cancer.” ..."
From the 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."
Mapping ‘Dark’ Regions of the Genome Illuminates How Cells Respond to Their Environment (original news release) "Previously unmapped sections of the genome explain how cells sense their mechanical environment and could open new paths for treating disease"
Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness (no public access)
Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness (preprint, open access)
Fig. 2.
CRISPRi screening reveals a MYH9 intron 3 mechanoenhancer that regulates MYH9 expression and cell contractility.
