Multiplex CRISPRa Reveals Cell-Specific Gene Regulation

The American researchers applied the novel approach to chronic myelogenous leukaemia cells (K562) and iPSC-derived excitatory neurons, revealing distinct regulatory patterns between cell types.

The framework used random combinations of gRNAs targeting promoters and enhancers. In K562 cells, the study identified specific enhancers that could upregulate autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes. Meanwhile, in neurons, the method uncovered regulatory elements active only in post-mitotic neurons, confirming cell-type specificity.

This research highlights the role of chromatin accessibility and trans-acting factors in gene activation via CRISPRa, as enhancers located in more open chromatin regions were consistently found to be more responsive to CRISPRa perturbations, facilitating successful gene upregulation.

The study was led by Jay Shendure and Nadav Ahituv from the University of Washington and the University of California, San Francisco, respectively. It was published today in Nature Communications.