Transposable elements become increasingly active in both cancerous and aging cells, driven by loss of DNA methylation as cells divide. Here we leverage the epigenomes of colon cancers with matched adjacent tissue, in addition to non-cancerous normals and cell line models, to assess the role of transposable elements as drivers or passengers in cancer development. Using the baseline of activity from normal and adjacent tissue, we show that the youngest subfamilies of the LINE1 (L1) family exhibit a degree of activity and recurrence across patients that goes beyond what is expected from hypomethylation and cell division, suggesting an additional mechanism of oncogenic reactivation. We characterize this mechanism and find that the loss of the tumor suppressor PLZF drives young L1 reactivation in a cell-division-independent manner. PLZF de-repression exposes abundant motifs for tumor core factors in the L1 5UTR. Active young L1s act as oncogenic enhancers, interacting with oncogenes via gained chromatin loops. We uncover oncogenic L1 reactivation as a hallmark of colon cancer, where young L1s activate universally in our cohort at high levels of recurrence, act as enhancers to oncogenes, and become wired into the core regulatory circuitry of colon cancer.
Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a translocation that creates the chimeric transcription factor PAX3-FOXO1 (P3F), which assembles de novo super enhancers to drive high levels of transcription of other core regulatory transcription factors (CRTFs). P3F recruits co-regulatory factors to super enhancers such as BRD4, which recognizes acetylated lysines via BET bromodomains. In this study, we demonstrate that inhibition or degradation of BRD4 leads to global decreases in transcription, and selective downregulation of CRTFs. We also show that the BRD4 degrader ARV-771 halts transcription while preserving RNA Polymerase II (Pol2) loops between super enhancers and their target genes, and causes the removal of Pol2 only past the transcriptional end site of CRTF genes, suggesting a novel effect of BRD4 on Pol2 looping. We finally test the most potent molecule, inhibitor BMS-986158, in an orthotopic PDX mouse model of FP-RMS with additional high-risk mutations, and find that it is well tolerated in vivo and leads to an average decrease in tumor size. This effort represents a partnership with an FP-RMS patient and family advocates to make preclinical data rapidly accessible to the family, and to generate data to inform future patients who develop this disease.
Core regulatory transcription factors (CR TFs) orchestrate the placement of super enhancers (SEs) to activate transcription of cell-identity specifying gene networks and are critical in promoting cancer. We defined the core regulatory circuitry of fusion positive rhabdomyosarcoma (FP-RMS, a cancer of childhood) in primary tumors and cell lines, which includes PAX3-FOXO1 (P3F), MYOD1, SOX8, MYCN and others. To find chemical probes able to selectively inhibit CR TF transcription, we screened the Structural Genomics Consortium epigenetic probe set by RNA-seq. We found that chemical probes along the acetylation-axis, and not the methylation-axis, are able to cause selective disruption of CR TF transcription. Inhibitors of HDACs (acetylation erasers), BRD4 (acetylation readers) and CBP/p300 (acetylation writers) were all able to selectively halt CR TF transcription. For HDACs, this raised a conundrum: why would too much histone acetylation, an active chromatin mark, stop transcription at CR TFs? ChIP-seq showed that CR TFs build SEs that have the largest quantities of histone acetylation and the enzymes that write acetylation (i.e., p300), yet paradoxically also harbor the highest amounts of the opposing histone deacetylases (HDACs). To investigate the architectural effects of disabling HDACs and causing hyper acetylation, we developed Absolute Quantification of Architecture (AQuA) HiChIP, revealing erosion of native SE contacts at CR TFs, and extensive aberrant contacts. This did not cause an elongation defect, but rather removed RNA Pol2 from core regulatory genetic elements and eliminated RNA-Pol2 phase condensates in 20 minutes. We further dissected the contribution of HDAC isoforms using a set of HDAC selective inhibitors, finding HDAC1/2/3 are co-essential to CR transcription. Using HAT inhibitors/degraders, we discovered a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in FP-RMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription. Overall, our data reveals a SE-specific need for balancing histone acetylation states to maintain SE architecture, Pol2 clustering in 3D, and CR TF transcription. Citation Format: Berkley E. Gryder, Diana Chin, Hyunmin Kim, Issra Osman. Histone acetylation axis in the control of RNA Pol2 clusters. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3726.
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