This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Human cells hold about two meters (6.6 feet) of DNA, folded and compacted to fit inside a nucleus. That packing is essential for life, but it creates a problem for scientists.
Some of the genes that control a cell's identity are buried so deep in tightly packed DNA that gene-targeting tools such as CRISPR activation, or CRISPRa, struggle to reach them. That problem lies at the heart of cell reprogramming, which converts one type of cell into another. Scientists can turn a patient's skin cells into neurons, heart cells or other hard-to-obtain cell types to study how a disease develops, test drugs for safety and effectiveness, and potentially grow replacement tissue the patient's immune system is less likely to reject.
But the process remains stubbornly inefficient. In mouse cells, often only a few percent of cells convert, and in human cells, the success rate can fall to a fraction of a percent. Now, UCLA researchers have found a physical way to improve those odds.
In a study published in Matter, the team describes a strategy that squeezes the nucleus for just milliseconds, temporarily loosening tightly packed DNA so CRISPRa can reach and switch on genes it would otherwise struggle to access. In mouse cells, the approach raised the share of skin cells that became neurons from about 3% with CRISPRa alone to about 40%. The biggest gains came when the squeeze was used as a priming step that made the cells more adaptable.
"Even when the reprogramming factors are inside the cell, the last mile of the problem is that they can't get access to the sites they need to bind to activate genes," said senior author Song Li, associate dean for graduate and professional education and a professor of bioengineering at the UCLA Samueli School of Engineering and a member of the UCLA Broad Stem Cell Research Center. "We are addressing that last-mile problem, which is accessibility." Nearly every cell in the body carries the same genome, yet a neuron looks and behaves nothing like a skin cell. The difference is in the epigenome, the layer of chemical and structural controls that decides which genes are open for use and which are shut.
Li compares it to a computer: The genome sequence is the hardware, and the epigenome is the operating system that determines what the machine actually does. Genes a cell doesn't need are packed away tightly in dense chromatin—the DNA and protein packaging inside the nucleus. A neuronal gene in a skin cell isn't normally used, so it's often stored this way.
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