An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer

Di Benedetto, C.; Tsark, A.; Acenas, D. D.; Thach, A.; Singal, A.; Opazo-Medallo, V.; Rodriguez, A.; El Zeini, M.; Zhang, H.; Park, C.; Gonzales-Velozo, H.; Weissman, I. L.; Betancur, P.

doi:10.1101/2025.11.05.684493

bioRxiv · 10.1101/2025.11.05.684493

An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer

Di Benedetto, C.·Tsark, A.·Acenas, D. D.·Thach, A.·Singal, A.·Opazo-Medallo, V.·Rodriguez, A.·El Zeini, M.·Zhang, H.·Park, C.·Gonzales-Velozo, H.·Weissman, I. L.·Betancur, P.

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Abstract

Highly accessible genomic super-enhancers often drive tumor-promoting programs, yet the impact of genomic variation within these regulatory elements remains unclear. Here, we identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. We discovered that a common germline insertion variant within the super-enhancer is associated with reduced chromatin accessibility at the super-enhancer locus. Deletion of the insertion in breast cancer cells increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, enhanced resistance to nutrient-deprivation-induced apoptosis (mediated by CD47), activation of senescence (driven by elevated LINC00636), delayed cell death, and reduced infiltration of CD80 pro-inflammatory macrophages, changes that represent tumor-promoting features. Together, our findings uncover a common insertion-deletion variant that fine-tunes the regulatory activity of a bifunctional super-enhancer, suggest a protective role for the insertion allele, and establish a novel function for LINC00636 in senescence and breast cancer.

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Di Benedetto, C., Tsark, A., Acenas, D. D., Thach, A., Singal, A., Opazo-Medallo, V., Rodriguez, A., El Zeini, M., Zhang, H., Park, C., Gonzales-Velozo, H., Weissman, I. L., Betancur, P.. 2025-11-07. An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer. https://doi.org/10.1101/2025.11.05.684493

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