Le Dilly, F. | Search bioRxiv

bioRxiv2025

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

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

genomics↗

bioRxiv2018

TFIIIC dynamically binds Alu elements to control gene expression through chromatin looping

Folding of the mammalian genome is governed by architectural proteins, such as CTCF. TFIIIC, a RNA polymerase III transcription factor, has been identified as an insulator but its role in genome topology is totally unknown. Here, we show that TFIIIC establishes long-range genomic interactions that affect gene expression. Upon serum starvation (SS), TFIIIC occupancy increases at Alu elements (AEs) near promoters of cell cycle-related genes. Bound AEs become H3K18 hyper-acetylated and fold to contact distal pre-loaded CTCF sites near other cell cycle genes. The promoters of these genes also become hyper-acetylated ensuring their basal transcription during SS and their increased expression during serum re-exposure. Ablation of TFIIIC or deletion of the TFIIIC-bound AE that loops to the G2/M cycling F (CCNF) locus affects its expression and nuclear positioning. These results illustrate a novel function of human TFIIIC in changing 3D genome topology through the epigenetic state of AEs.\n\nHighlightsO_LISerum starvation enhances TFIIIC binding to Alu Elements (AEs) near cell cycle genes\nC_LIO_LIBinding of TFIIIC increases H3K18 acetylation over the bound AE\nC_LIO_LITFIIIC-mediated looping to distal genes favors their reactivation upon serum addition\nC_LIO_LILong-range TFIIIC interactions tune cell cycle genes expression through nuclear repositioning\nC_LI\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC=\"FIGDIR/small/455733_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@917ee4org.highwire.dtl.DTLVardef@21d0fborg.highwire.dtl.DTLVardef@1f1a17org.highwire.dtl.DTLVardef@1e9df24_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗