PARP1 Regulates 3D Structure and Function of Super-Enhancers and Hormone-Control Regions in Breast Cancer Cells

Baccara, H.; Le Dilly, F.; Carnevali, D.; Font-Mateu, J.; Moreta, C.; Carbonell-Caballero, J.; Teichmann, M.; Beato, M.; Wright, R. H. G.; Ferrari, R.

doi:10.1101/2025.08.01.668155

bioRxiv · 10.1101/2025.08.01.668155

PARP1 Regulates 3D Structure and Function of Super-Enhancers and Hormone-Control Regions in Breast Cancer Cells

Baccara, H.·Le Dilly, F.·Carnevali, D.·Font-Mateu, J.·Moreta, C.·Carbonell-Caballero, J.·Teichmann, M.·Beato, M.·Wright, R. H. G.·Ferrari, R.

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Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) has been linked to various genomic pathways and in the maintenance of genomic stability. PARP1 has also been postulated to regulate cis-regulatory elements, but the mechanisms remain largely unknown. Here, we employed genomic approaches to show how PARP1 occupies Super-Enhancers (SEs) of luminal A T47D breast cancer cells and how some PARP1 is dynamically relodged by progesterone at hormone-control regions (HCRs). Disruption of PARP1 causes transcriptome reprogramming, altering the expression of both SE-associated and HCRs-regulated genes. This is achieved through a dual coordinated action in the establishment of long-range and intra-TADs chromatin loops, which are lost upon PARP1 ablation, but enforced by its catalytic inhibition. We show that PARP1 also plays a role in regulation of chromatin compartments. Our results reveal PARP1, as a new chromatin looper and compartments organizer controlling SEs and HCRs genes linked to cell identity and hormonal response in breast cancer cells via 3D genome organization. Highlights (Separate document)O_LIPARP1 occupies cell specific super-enhancers and hormone-control regions. C_LIO_LILoss of PARP1 alters the cell identity and progestin-induced gene expression signature. C_LIO_LIGene expression changes upon PARP1 loss relay on altered 3D chromatin looping and compartments. C_LI eTOC blurbWe have discovered that the nuclear repair protein and cancer drug target; PARP1 is preferentially bound at super-enhancers. The binding of PARP1 is essential for the underlying, cell specific gene expression program and the 3D structure of the chromatin surrounding the super-enhancer regions. Graphical abstractSeparate document O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/668155v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@1da9027org.highwire.dtl.DTLVardef@2e1966org.highwire.dtl.DTLVardef@8582eaorg.highwire.dtl.DTLVardef@155e77b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Baccara, H., Le Dilly, F., Carnevali, D., Font-Mateu, J., Moreta, C., Carbonell-Caballero, J., Teichmann, M., Beato, M., Wright, R. H. G., Ferrari, R.. 2025-08-02. PARP1 Regulates 3D Structure and Function of Super-Enhancers and Hormone-Control Regions in Breast Cancer Cells. https://doi.org/10.1101/2025.08.01.668155

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