A Multi-omic Dissection of Super-enhancer Driven Oncogenic Gene Expression Programs in Ovarian Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 22

PMID 35869079

Authors

Michael R Kelly

Kamila Wisniewska

Matthew J Regner

Michael W Lewis

Andrea A Perreault

Eric S Davis

Douglas H Phanstiel

Joel S Parker

Hector L Franco

Affiliations

Soon will be listed here.

Abstract

The human genome contains regulatory elements, such as enhancers, that are often rewired by cancer cells for the activation of genes that promote tumorigenesis and resistance to therapy. This is especially true for cancers that have little or no known driver mutations within protein coding genes, such as ovarian cancer. Herein, we utilize an integrated set of genomic and epigenomic datasets to identify clinically relevant super-enhancers that are preferentially amplified in ovarian cancer patients. We systematically probe the top 86 super-enhancers, using CRISPR-interference and CRISPR-deletion assays coupled to RNA-sequencing, to nominate two salient super-enhancers that drive proliferation and migration of cancer cells. Utilizing Hi-C, we construct chromatin interaction maps that enable the annotation of direct target genes for these super-enhancers and confirm their activity specifically within the cancer cell compartment of human tumors using single-cell genomics data. Together, our multi-omic approach examines a number of fundamental questions about how regulatory information encoded into super-enhancers drives gene expression networks that underlie the biology of ovarian cancer.

Citing Articles

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References

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

Franco H, Nagari A, Malladi V, Li W, Xi Y, Richardson D . Enhancer transcription reveals subtype-specific gene expression programs controlling breast cancer pathogenesis. Genome Res. 2017; 28(2):159-170. PMC: 5793780. DOI: 10.1101/gr.226019.117. View

Kim T, Shiekhattar R . Architectural and Functional Commonalities between Enhancers and Promoters. Cell. 2015; 162(5):948-59. PMC: 4556168. DOI: 10.1016/j.cell.2015.08.008. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Ma Q, Yang F, Mackintosh C, Jayani R, Oh S, Jin C . Super-Enhancer Redistribution as a Mechanism of Broad Gene Dysregulation in Repeatedly Drug-Treated Cancer Cells. Cell Rep. 2020; 31(3):107532. DOI: 10.1016/j.celrep.2020.107532. View

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

Wang L, Wang S, Li W . RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012; 28(16):2184-5. DOI: 10.1093/bioinformatics/bts356. View

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

Lewis M, Li S, Franco H . Transcriptional control by enhancers and enhancer RNAs. Transcription. 2019; 10(4-5):171-186. PMC: 6948965. DOI: 10.1080/21541264.2019.1695492. View

10.

Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R . Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013; 9(8):e1003118. PMC: 3738458. DOI: 10.1371/journal.pcbi.1003118. View

11.

Bonifacio V . Ovarian Cancer Biomarkers: Moving Forward in Early Detection. Adv Exp Med Biol. 2020; 1219:355-363. DOI: 10.1007/978-3-030-34025-4_18. View

12.

Granja J, Corces M, Pierce S, Bagdatli S, Choudhry H, Chang H . ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat Genet. 2021; 53(3):403-411. PMC: 8012210. DOI: 10.1038/s41588-021-00790-6. View

13.

Weintraub A, Li C, Zamudio A, Sigova A, Hannett N, Day D . YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017; 171(7):1573-1588.e28. PMC: 5785279. DOI: 10.1016/j.cell.2017.11.008. View

14.

Fulco C, Munschauer M, Anyoha R, Munson G, Grossman S, Perez E . Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science. 2016; 354(6313):769-773. PMC: 5438575. DOI: 10.1126/science.aag2445. View

15.

Sabari B, DallAgnese A, Boija A, Klein I, Coffey E, Shrinivas K . Coactivator condensation at super-enhancers links phase separation and gene control. Science. 2018; 361(6400). PMC: 6092193. DOI: 10.1126/science.aar3958. View

16.

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

17.

Coetzee S, Shen H, Hazelett D, Lawrenson K, Kuchenbaecker K, Tyrer J . Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci. Hum Mol Genet. 2015; 24(13):3595-607. PMC: 4459387. DOI: 10.1093/hmg/ddv101. View

18.

Durand N, Shamim M, Machol I, Rao S, Huntley M, Lander E . Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. Cell Syst. 2016; 3(1):95-8. PMC: 5846465. DOI: 10.1016/j.cels.2016.07.002. View

19.

Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo R, Croce C . Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1982; 79(24):7824-7. PMC: 347441. DOI: 10.1073/pnas.79.24.7824. View

20.

Franzen O, Gan L, Bjorkegren J . PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database (Oxford). 2019; 2019. PMC: 6450036. DOI: 10.1093/database/baz046. View