Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins

Da Xu, Swen Besselink, Gokul N. Ramadoss, Philip H. Dierks, Justin P. Lubin, Rithu K. Pattali, Jinna I. Brim, Anna E. Christenson, Peter J. Colias, Izaiah J. Ornelas, Carolyn D. Nguyen, Sarah E. Chasins, Bruce R. Conklin and James K. Nuñez ()
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Da Xu: University of California
Swen Besselink: University of California
Gokul N. Ramadoss: Gladstone Institutes
Philip H. Dierks: Gladstone Institutes
Justin P. Lubin: University of California
Rithu K. Pattali: University of California
Jinna I. Brim: University of California
Anna E. Christenson: University of California
Peter J. Colias: University of California
Izaiah J. Ornelas: University of California
Carolyn D. Nguyen: University of California
Sarah E. Chasins: University of California
Bruce R. Conklin: Gladstone Institutes
James K. Nuñez: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Programmable epigenome editors modify gene expression in mammalian cells by altering the local chromatin environment at target loci without inducing DNA breaks. However, the large size of CRISPR-based epigenome editors poses a challenge to their broad use in biomedical research and as future therapies. Here, we present Robust ENveloped Delivery of Epigenome-editor Ribonucleoproteins (RENDER) for transiently delivering programmable epigenetic repressors (CRISPRi, DNMT3A-3L-dCas9, CRISPRoff) and activator (TET1-dCas9) as ribonucleoprotein complexes into human cells to modulate gene expression. After rational engineering, we show that RENDER induces durable epigenetic silencing of endogenous genes across various human cell types, including primary T cells. Additionally, we apply RENDER to epigenetically repress endogenous genes in human stem cell-derived neurons, including the reduction of the neurodegenerative disease associated V337M-mutated Tau protein. Together, our RENDER platform advances the delivery of CRISPR-based epigenome editors into human cells, broadening the use of epigenome editing in fundamental research and therapeutic applications.

Date: 2025
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DOI: 10.1038/s41467-025-63167-x

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