Comprehensive dissection of cis-regulatory elements in a 2.8 Mb topologically associated domain in six human cancers

Christina M. Caragine, Victoria T. Le, Meer Mustafa, Bianca Jay Diaz, John A. Morris, Simon Müller, Alejandro Mendez-Mancilla, Evan Geller, Noa Liscovitch-Brauer and Neville E. Sanjana ()
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Christina M. Caragine: New York Genome Center
Victoria T. Le: New York Genome Center
Meer Mustafa: New York Genome Center
Bianca Jay Diaz: New York Genome Center
John A. Morris: New York Genome Center
Simon Müller: New York Genome Center
Alejandro Mendez-Mancilla: New York Genome Center
Evan Geller: New York Genome Center
Noa Liscovitch-Brauer: New York Genome Center
Neville E. Sanjana: New York Genome Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Cis-regulatory elements (CREs), such as enhancers and promoters, are fundamental regulators of gene expression and, across different cell types, the MYC locus utilizes a diverse regulatory architecture driven by multiple CREs. To better understand differences in CRE function, we perform pooled CRISPR inhibition (CRISPRi) screens to comprehensively probe the 2.8 Mb topologically-associated domain containing MYC in 6 human cancer cell lines with nucleotide resolution. We map 32 CREs where inhibition leads to changes in cell growth, including 8 that overlap previously identified enhancers. Targeting specific CREs decreases MYC expression by as much as 60%, and cell growth by as much as 50%. Using 3-D enhancer contact mapping, we find that these CREs almost always contact MYC but less than 10% of total MYC contacts impact growth when silenced, highlighting the utility of our approach to identify phenotypically-relevant CREs. We also detect an enrichment of lineage-specific transcription factors (TFs) at MYC CREs and, for some of these TFs, find a strong, tumor-specific correlation between TF and MYC expression not found in normal tissue. Taken together, these CREs represent systematically identified, functional regulatory regions and demonstrate how the same region of the human genome can give rise to complex, tissue-specific gene regulation.

Date: 2025
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DOI: 10.1038/s41467-025-56568-5

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