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SDIRSACR Oncology Insights

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Epi-CRISPR tool: A synthetic epigenetic editing platform for cell reprogramming and therapeutic targeting
in cancer

Melita Vidaković

Department of Molecular Biology, Institute for Biological Research "Siniša Stanković", National Institute of the Republic of Serbia,
University of Belgrade, Belgrade, Serbia

Understanding and manipulating the epigenetic regulation of cell identity and disease progression holds immense
therapeutic potential, particularly in light of recent advances in programmable epigenetic editors. The advent of CRISPR-
based epigenetic systems, including dCas9-fused methyltransferases, histone modifiers, and chromatin remodelers,
has expanded our ability to modify gene expression without altering the DNA sequence, offering novel routes for
disease modeling and intervention.
Here, we present Epi-CRISPR, a next-generation synthetic epigenetic editing platform built on the latest developments
in CRISPR/dCas9 technologies. Our system utilizes a controllable vector to precisely and reversibly edit epigenetic
marks such as DNA methylation at targeted genomic loci. It has already been used to reprogram pancreatic α-cells
into insulin-producing cells by modifying the epigenetic and transcriptional states of the ARX gene, a master regulator
of pancreatic lineage specification. This work builds upon recent studies demonstrating that targeted reactivation or
suppression of developmental genes can drive functional cell conversion, positioning Epi-CRISPR as a powerful tool for
diabetes therapy.
Additionally, we explore Epi-CRISPR's application in inducing a BRCAness phenotype in triple-negative breast cancer
(TNBC) cells lacking BRCA1 mutations. By directing locus-specific DNA methylation to the BRCA1 promoter, we
suppress gene expression and investigate associated chromatin changes using high-resolution EPIC methylation. We
further examine the interplay between DNA methylation and histone marks (H3K4me3, H3K9me3, H3K27me3) using
ACT-seq methodology. This approach leverages recent findings on the dynamic cross-talk between DNA and histone
modifications in cancer progression and therapy resistance.
By enabling programmable, non-mutagenic control over gene regulation, Epi-CRISPR holds promise as a clinically
translatable strategy for enhancing cell plasticity, sensitizing tumors to targeted therapy (e.g., PARP inhibitors), and
uncovering fundamental mechanisms of epigenetic memory and identity. Furthermore, epigenetic editing holds promise
in overcoming drug resistance, modulating tumor immunogenicity, and personalizing treatment regimens based on
epigenetic signatures. As epigenome-targeting tools become more refined and clinically compatible, epigenetic editing
is poised to complement or even replace traditional therapies in selected cancer subtypes.

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