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bioRxiv · 10.1101/2023.11.20.567880

Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes

Wang, Y.·Armendariz, D. A.·Wang, L.·Zhao, H.·Xie, S.·Hon, G. C.
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Abstract

Genetic studies have associated thousands of enhancers with breast cancer. However, the vast majority have not been functionally characterized. Thus, it remains unclear how variant-associated enhancers contribute to cancer. Here, we perform single-cell CRISPRi screens of 3,512 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of >500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of variant-associated enhancers disrupts breast cancer gene programs. We observe variant-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple variant-associated enhancers indirectly regulate TP53. Comparative studies illustrate sub-type specific functions between enhancers in ER+ and ER- cells. Finally, we developed the pySpade package to facilitate analysis of single-cell enhancer screens. Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.

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Wang, Y., Armendariz, D. A., Wang, L., Zhao, H., Xie, S., Hon, G. C.. 2023-11-20. Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes. https://doi.org/10.1101/2023.11.20.567880

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