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Non-Coding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies

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Non-Coding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies Author Manuscript Published OnlineFirst on March 18, 2020; DOI: 10.1158/2159-8290.CD-19-1128 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Non-Coding Variants Connect Enhancer Dysregulation with Nuclear Receptor Signaling in Hematopoietic Malignancies Kailong Li1,2,5, Yuannyu Zhang1,2,5, Xin Liu1,2,5, Yuxuan Liu1,2,5, Zhimin Gu1,2, Hui Cao1,2, Kathryn E. Dickerson1,2, Mingyi Chen3, Weina Chen3, Zhen Shao4, Min Ni1, Jian Xu1,2,* 1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 2Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 4Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 5These authors contributed equally *Corresponding Author: [email protected] (J.X.) Mailing address: 6000 Harry Hines Blvd. C. Kern Wildenthal Research Building – NL12.138B UT Southwestern Medical Center Dallas, Texas 75390-8502 Phone: 214-648-6125 Running Title: Non-Coding Variants in Hematopoietic Malignancies Keywords: Non-Coding Variants, Enhancers, Epigenetics, Leukemia, Nuclear Receptor Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 1 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 18, 2020; DOI: 10.1158/2159-8290.CD-19-1128 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Mutations in protein-coding genes are well established as the basis for human cancer, yet it remains elusive how alterations within non-coding genome, a substantial fraction of which contain cis-regulatory elements (CREs), contribute to cancer pathophysiology. Here, we developed an integrative approach to systematically identify and characterize non-coding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage-associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated non- coding variants. By enhanced CRISPR/dCas9-based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor suppressive CREs in human leukemia. Non-coding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently co-localize with non-coding variants across cancer types. Hence, recurrent non-coding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies. SIGNIFICANCE We describe an integrative approach to identify non-coding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor suppressive cis-elements including KRAS and PER2 enhancers. Our findings support a model that non-coding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies. 2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 18, 2020; DOI: 10.1158/2159-8290.CD-19-1128 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Advances in genome sequencing have provided critical insights into the role of pathogenic DNA alterations as cancer drivers. However, current efforts are focused on protein-coding sequences (or exomes) consisting of only about 1% of human genome. It remains unclear how alterations within non-coding genome contribute to cancer pathophysiology. Similarly, genome-wide genotype-phenotype association studies continue to reveal non-coding sequences that are altered in human diseases, although identification of causal elements remains difficult impeding drug development and therapeutics. Enhancers are non-coding cis-regulatory elements (CREs) that determine cell identity by coordinating spatiotemporal gene expression. Major progress has been made to identify candidate enhancers by genome-wide mapping of enhancer-associated histone modifications including H3-Lys27 acetylation (H3K27ac) and H3-Lys4 mono-methylation (H3K4me1), transcription factors (TFs), and chromatin features (1-4). The biological significance of enhancers is underscored by gene expression studies showing the deterministic role of enhancers in directing cell-type-specific transcription (2,5-7). Highly marked clusters of enhancers or super-enhancers associated with developmental or cancer-related genes have been identified in various cell types (8-11). These studies suggest a model that a small set of lineage-defining enhancers determine cell identity in development and cancer. Emerging evidence points to a critical role of non-coding regulatory variants as cancer drivers (12,13). For instance, recurrent mutations in the TERT promoter create new binding motifs for ETS family TFs to enhance gene transcription in familial and sporadic melanoma (14,15). In the context of leukemia, recurrent non-coding mutations upstream of the TAL1 proto-oncogene introduce de novo binding sites for the MYB oncoprotein in T-cell leukemia. MYB associates with these sites with CBP, RUNX1 and TAL1 to create an oncogenic super-enhancer and activates TAL1 expression (16). In another example, a single chromosomal rearrangement repositions a GATA2 enhancer to ectopically activate EVI1 and confer GATA2 haploinsufficiency in inv(3)/t(3;3) acute myeloid leukemia (AML) (17). These studies raise important questions about the extent to which non-coding variants contribute to cancer development, and how they work. Moreover, the functional impact of non-coding somatic mutations found in cancer genome sequencing has not been systematically investigated or validated. The main challenges are to distinguish candidate non-coding cancer drivers from numerous non-functional passenger mutations and to establish causality of non-coding variants in cancer pathophysiology. Human nuclear receptors (NRs) are a family of signaling-activated TFs that play integral roles in development and cancer (18). The peroxisome proliferator-activated receptors (PPARα, β/δ, and γ) function as obligate heterodimers with the retinoid X receptors (RXRα, β, and γ) in the absence of ligands and bind to hormone response elements together with corepressor proteins. The retinoic acid receptors (RARα, β, and γ) also heterodimerize with RXRs and bind 3 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 18, 2020; DOI: 10.1158/2159-8290.CD-19-1128 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. constitutively to DNA in the absence of ligands. Binding of agonist ligands to PPAR/RXR or RAR/RXR complexes leads to dissociation of corepressors and recruitment of coactivator proteins, resulting in transcriptional activation of downstream target genes. The ability of NRs to rapidly and dynamically respond to various developmental and environmental clues by modulating gene programs makes them versatile cellular ‘sensors’. As such, NRs have historically served as biomarkers for classification of several solid tumors including breast and prostate cancers and targets for hormone therapy (19). In the hematopoietic system, the fusion oncogene PML-RARA provides a diagnostic biomarker for acute promyelocytic leukemia (APL) and the molecular basis for oncoprotein-targeted therapy (20). In this work, we developed an integrative approach to identify recurrent non-coding variants by targeted resequencing of cis-regulatory elements in human leukemia. A major limiting step towards understanding non-coding cancer variants is the lack of a high-throughput platform to assess their functional effects. To that end, we employed enhanced dCas9-based epigenetic editing and performed CRE perturbation screens. This revealed a cohort of variant-associated oncogenic and tumor suppressive CREs, and established a new molecular link between non- coding regulatory variants and nuclear receptor signaling in modifying gene programs in hematopoietic malignancies. RESULTS Identification of non-coding DNA alterations by targeted CRE resequencing To determine whether human leukemia genomes harbor recurrent non-coding alterations, we generated mutational landscapes of CREs by targeted resequencing (Fig. 1A; Fig. S1). We first annotated hematopoietic lineage-associated CREs based on genome-wide profiling of active enhancer or promoter-associated H3K27ac in various normal and diseased hematopoietic cell types, including CD34+ hematopoietic stem/progenitor cells (HSPCs), lymphocytes, macrophages, monocytes, erythroblasts, lymphoma, acute lymphoblastic leukemia (ALL), and AML (total 72 ChIP-seq datasets for 51 normal and 21 disease samples, respectively; Table S1 and Fig. S1A,B). We then designed a
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