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Chromatin Accessibility Changes at Intergenic Regions Associated with Ovarian Cancer Drug Resistance

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Chromatin Accessibility Changes at Intergenic Regions Associated with Ovarian Cancer Drug Resistance Gallon et al. Clin Epigenet (2021) 13:122 https://doi.org/10.1186/s13148-021-01105-6 RESEARCH Open Access Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance John Gallon1†, Erick Loomis1†, Edward Curry1, Nicholas Martin2, Leigh Brody3, Ian Garner1, Robert Brown1,4* and James M. Flanagan1* Abstract Background: Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prog- nosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. Results: Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. Conclusions: Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models. Keywords: Cancer, Chemotherapy, Drug resistance, Epigenomics, Ovarian Background chemotherapy, they will eventually relapse with disease Platinum-based chemotherapeutics, such as cisplatin and that fails to respond to treatment leading to poor survival carboplatin, are clinically important frst line therapies [3, 4]. Understanding the changes that occur in platinum- in the treatment of a wide variety of solid cancers [1, 2]. resistant tumors is essential for rational approaches to Tese drugs exert their DNA damaging, cytotoxic efect circumvent resistance and developing molecularly tar- by the formation of platinum-DNA adducts, inter- and geted agents for use in recurrent cancers. intra-strand cross-links, which induce cell death through Epigenetic mechanisms play a key role in the develop- a number of pathways if the adduct is not repaired [3]. ment of platinum-resistance and drug tolerance [5]. Cells While many patients initially respond to platinum-based surviving cisplatin exposure, such as transient drug tol- erant persisters, or drug-resistant cells surviving cispl- atin selection have genome wide epigenetic alterations *Correspondence: [email protected]; [email protected]. [5-8]. Drug-tolerant persisters exhibit a repressed chro- †John Gallon and Erick Loomis joint frst authors. 1 Department of Surgery and Cancer, Ovarian Cancer Action Research matin state and can serve as founders for further genetic Centre, Imperial College London, London W12 8EE, UK and epigenetic change leading to resistance [7, 9-11]. Full list of author information is available at the end of the article Te promoters of genes susceptible to hypermethylation Robert Brown and James M. Flanagan joint corresponding authors. in ovarian tumors during the emergence of resistance © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gallon et al. Clin Epigenet (2021) 13:122 Page 2 of 15 to platinum resistance are marked by H3K27 and H3K4 Damage-seq [22, 23]. In Damage-seq, cisplatin-damaged bivalent methylation domains present in tumor cells DNA fragments are immunoprecipitated using an anti- pre-chemotherapy, further emphasizing the relationship body specifc to platinum-bound DNA prior to sequenc- between chromatin states and epigenetic adaptation to ing using a library preparation protocol dependent on the platinum treatment [12]. Epigenome profling of ovar- stalling of DNA polymerase by DNA adducts. Fragments ian cell line models selected in vitro for platinum resist- without adducts which are non-specifcally bound by the ance has suggested a role for distal super-enhancers immunoprecipitation step are removed by subtractive (SEs) and their gene targets in maintain the transcrip- hybridization prior to sequencing. Tis method provides tional program of the platinum-resistant state [13, 14]. accurate and strand-specifc mapping of DNA damage, Tese studies highlight the multi-factorial nature of the but is dependent on immunoprecipitation and therefore transcriptional states driving platinum resistance, while heavily infuenced by the sensitivity and specifcity of the identifying SEs that play a critical role in transcriptional antibody used and the conditions for subtractive hybridi- regulation of platinum resistance during in vitro selec- zation. Pt-exo-seq avoids these potential complications tion. However, it is still poorly understood whether such while still providing accurate and strand-specifc map- changes at SEs occur following in vivo selection follow- ping at high resolution. ing platinum-based chemotherapy of patients’ tumors as they develop clinical resistance. Results Using matched chemosensitive and chemoresistant Chromatin conformation in matched resistant lines ovarian cancer cell lines isolated from high-grade serous following platinum‑based treatment ovarian cancer patients before and following treatment, We studied chromatin conformation by ATAC-seq in we examined the relationship between chromatin acces- three isogenic pairs of sensitive and resistant human sibility, platinum-DNA adduct distribution, and chemo- ovarian cell lines. PEO1 and PEO4 were both isolated therapy resistance. To examine further the potential from the same patient diagnosed with high-grade serous functional signifcance of any changes observed, we have ovarian cancer (HGSOC) following platinum-based correlated chromatin changes, identifed using ATAC- chemotherapy, but before and after the clinical develop- seq, between the lines at gene promoters, CpG islands, ment of resistance [25]. PEA1 and PEA2 were isolated clusters of cis-regulatory elements (COREs) and other from ascites of a patient with HGSOC prior to platinum genomic regions with changes in gene expression. chemotherapy and after relapse with resistant disease Te platinum atom of cisplatin can form covalent [25]. A2780cp70 (abbreviated to CP70) is an in vitro bonds to the N7 positions of purine bases and the density derived platinum-resistant derivative of the ovarian cell of GG dinucleotides is considered the main factor infu- line A2780 [24]. Te characteristics and sensitivities of encing distribution of platinum adducts [15]. However, the cell line to cisplatin are summarized in Additional chromatin states could also afect the pattern of cisplatin fle 1: Table S1. cross-linking [16, 17]. Indeed, epigenetic therapies, such Chromatin accessibility profles were compared as histone deacetylase (HDAC) inhibitors, can increase between the sensitive and resistant lines in each pair, the accessibility of chromatin to cisplatin through global based on ATAC-seq data produced in triplicate. ATAC- chromatin decompaction, leading to enhanced cell death seq reads were assigned to 1 Kb windows tiling across the [18]. Given the known roles for chromatin in mediating reference genome (hg19). FPKM values (Fragments Per the emergence of drug resistance and since chromatin Kilobase of DNA, per Million mapped reads of sequenc- changes might infuence the formation and efect of plati- ing library) were calculated for each window, in each num adducts, we aimed to examine platinum-adduct dis- replicate. Individual windows were called diferentially tribution in the genome of ovarian cancer cells and relate accessible based on a log2 fold change in coverage in the this to chromatin conformation and gene expression. sensitive-to-resistant lines > ±2 and moderated t test We developed Pt-exo-seq to map platinum adducts, FDR < 0.001. Substantial alterations to the landscape of genome-wide by adapting methods for exonuclease map- chromatin accessibility were found in all three resistant ping of transcription factor binding sites [19-21]. Pt-exo- lines compared to their sensitive counterparts, afecting seq is primarily based on the inhibition of exonuclease 297 windows (0.009%) of the genome in the A2780 pair activity by the bulky platinum adduct and the subsequent (Fig. 1a), 8950 windows (0.27%) of the genome in the removal of the adduct by
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