EFRI CEE: Optically Controlled Localized Epigenetic Chromatin Remodeling with Photoactivatable CRISPR-dCas9

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There are many cancers which come back after apparent recovery and there are others which initially respond to chemotherapy but eventually become treatment-resistant. Along with genetic mutations, this often happens due to epigenetic alterations that do not involve the DNA coding sequence but instead result in a change in gene activity deactivating cellular antitumor systems and activating oncogenes. A recently developed modified form of the gene editing technology called epigenetic CRISPR has the potential to influence those alterations providing effective treatment for recurrent and treatment-resistant cancers.Presently, one of the biggest challenges to using CRISPR that prevents it from being implemented on a systemic level is the concern for off-target effects in normal cells that do not need to be modified. Thus, developing a CRISPR system capable of dynamic control of gene activation in space and time would be a critically important step. To address that, light activated CRISPR was introduced recently. Unfortunately, its major limitation is the need to use blue or UV light, severely reducing the activation penetration depth and, in the case of UV, raising safety concerns. This team address this problem by developing CRISPR-dCas9 which is compatible with NIR light activation, an option not currently available. The proposed light activated chromatin remodeling approach is transformative since it could lead to the development of highly effective targeted epigenetic cancer therapies not prone to off-target activity. In addition, it could also serve as a non-invasive optogenetic tool which does not require a fiber optic implantation and could have various applications in oncology, neurology, ophthalmology, and cardiology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.