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Mapping of Transcription Factor Motifs in Active Chromatin Identifies IRF5 As Key Regulator in Classical Hodgkin Lymphoma

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Mapping of Transcription Factor Motifs in Active Chromatin Identifies IRF5 As Key Regulator in Classical Hodgkin Lymphoma Mapping of transcription factor motifs in active PNAS PLUS chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma Stephan Krehera,b,1, M. Amine Bouhlelc,1, Pierre Cauchyd, Björn Lamprechta,b,e, Shuang Lia,b, Michael Grauf, Franziska Hummela,b, Karl Köcherta,b, Ioannis Anagnostopoulosg, Korinna Jöhrensg, Michael Hummele,g, John Hiscotth, Sören-Sebastian Wenzelb, Peter Lenzf, Markus Schneideri, Ralf Küppersi, Claus Scheidereita, Maciej Giefingj,k, Reiner Siebertj, Klaus Rajewskya, Georg Lenzb, Peter N. Cockerilld, Martin Janza,b, Bernd Dörkena,b,e, Constanze Boniferd,2, and Stephan Mathasa,b,e,2 aMax-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; bHematology, Oncology, and Tumor Immunology, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany; cLeeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, United Kingdom; dSchool of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; eGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; fDepartment of Physics, Philipps University, 35052 Marburg, Germany; gInstitute of Pathology, Charité– Universitätsmedizin Berlin, 10117 Berlin, Germany; hVaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL 34987; iInstitute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122 Essen, Germany; jInstitute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; and kInstitute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland Edited by Louis M. Staudt, National Cancer Institute, National Institutes of Health, Bethesda, MD, and approved September 4, 2014 (received for review April 17, 2014) Deregulated transcription factor (TF) activities are commonly ob- lineages. However, the nature of the TFs initiating and maintaining served in hematopoietic malignancies. Understanding tumorigene- HRS-specific gene expression remains poorly understood. sis therefore requires determining the function and hierarchical role As an unbiased approach for the identification of deregulated of individual TFs. To identify TFs central to lymphomagenesis, we TF activities central to lymphoma biology, we identified HL-specific identified lymphoma type-specific accessible chromatin by global accessible chromatin regions by global mapping of DNaseI hy- mapping of DNaseI hypersensitive sites and analyzed enriched TF- persensitive sites (DHSs). DHSs mark cis-regulatory elements MEDICAL SCIENCES binding motifs in these regions. Applying this unbiased approach to bound by TF complexes (9) and differ between normal and classical Hodgkin lymphoma (HL), a common B-cell–derived lym- malignant cells (10, 11). We then performed an unbiased genome- phoma with a complex pattern of deregulated TFs, we discovered wide search for TF binding motifs enriched within HRS-specific interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 Significance initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating Human lymphomas and leukemias are characterized by mo- with NF-κB to activate essential characteristic features of HL. Our lecular and structural alterations of transcription factors (TFs). strategy efficiently identified a lymphoma type-specific key regula- The identification of such deregulated TFs is therefore central tor and uncovered a tumor promoting role of IRF5. to the understanding of lymphomagenesis. We addressed this question in classical Hodgkin lymphoma (HL), a common B-cell– ranscription factor (TF) activities have to be tightly con- derived malignancy that is one of the most prominent examples trolled because their aberrant regulation alters tissue-specific for complex patterns of deregulated TFs including the activation T κ gene expression programs and contributes to cancer pathogenesis. of NF- B or AP-1 and a profound deregulation of lineage- κ Therefore, the identification of altered TF activities in malig- specific TFs. We found that IRF5 together with NF- Binduces nancies is of crucial importance to understand malignant trans- a number of HL characteristic features in non-Hodgkin cells, formation and to develop new treatment strategies. Deregulated such as expression of cytokines and chemokines or AP-1 acti- TF activities are commonly observed in hematopoietic malignan- vation. Our work exemplifies how the global lymphoma type- cies including human lymphomas and leukemias, and the link specific characterization of TF activities can improve the between structural or functional alterations in TFs and malignant understanding of tumor biology. transformation has been documented in various in vitro and in – Author contributions: S.K., M.A.B., P.C., S.L., G.L., P.N.C., M.J., C.B., and S.M. designed vivo studies (1 3). Apart from the direct modulation of cellular research; S.K., M.A.B., P.C., B.L., S.L., F.H., S.-S.W., and M.S. performed research; S.K., processes like cellular growth or cell death, alterations of the ac- M.A.B., P.C., B.L., S.L., M. Grau, F.H., K.K., I.A., K.J., M.H., J.H., S.-S.W., P.L., M.S., R.K., C.S., tivity of even single TFs might enforce malignant transformation M. Giefing, R.S., K.R., G.L., P.N.C., M.J., B.D., C.B., and S.M. analyzed data; C.B. and S.M. by switching differentiation programs and consequently altering wrote the paper; S.K., M.A.B., P.C., R.K., C.S., M. Giefing, R.S., K.R., G.L., P.N.C., M.J., and B.D. contributed to writing of the manuscript; K.K. analyzed microarray data; I.A. and K.J. the cellular fate of the respective cells, as exemplarily demon- performed and interpreted IHC analyses; J.H. provided material; J.H., C.S., R.S., K.R., and strated for the B-lymphoid TF PAX5 (4, 5). B.D. interpreted data; and C.B. and S.M. supervised the project. Among lymphoid malignancies, one of the most prominent The authors declare no conflict of interest. examples for complex patterns of deregulated TFs is classical This article is a PNAS Direct Submission. Hodgkin lymphoma (HL), a common B cell-derived malignancy (6). Freely available online through the PNAS open access option. Pathogenic hallmarks of the malignant Hodgkin/Reed-Sternberg Data deposition: The datasets reported in the manuscript have been deposited in the (HRS) cells of HL include the constitutive activation of TFs that Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. are only transiently activated in normal B cells, such as nuclear GSE51726, GSE51813, GSE51717, and GSE51719). κ factor kappa B (NF- B) or activator protein-1 (AP-1), and a pro- 1S.K. and M.A.B. contributed equally to this work. – found deregulation of lineage-specific TFs such as E2A (6 8). 2To whom correspondence may be addressed. Email: [email protected] or stephan. Thus, although originating from B-lymphoid cells, HRS cells have [email protected]. lost their B cell-specific gene expression pattern and instead up- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. regulate expression of genes characteristic for other hematopoietic 1073/pnas.1406985111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1406985111 PNAS | Published online October 6, 2014 | E4513–E4522 Downloaded by guest on October 1, 2021 accessible chromatin and functionally analyzed the role of the Identification of TF-Binding Motifs Enriched in HRS Cell-Specific corresponding factors. The identification of binding motifs for the Accessible Chromatin Regions. To identify TFs responsible for TFs AP-1, NF-κB, and STAT in HL-specific accessible chromatin the HRS-specific gene expression program, we searched for TF confirmed their essential role for HL biology (6). In addition, we DNA binding motifs specifically enriched in HRS-specific DHSs, revealed that IFN regulatory factor (IRF) binding motifs are using both L1236 and L428 cells as references (Fig. 2 A and B). among the top enriched motifs in HL. We detected in HRS cells an In the B (NH)-specific DHS signature (Fig. 1D; A), binding abundant expression and increased activity of IRF5, which is an motifs for TFs important for the B-cell program such as E-box IRF TF family member that plays a central role in Toll-like re- and OCT motifs (18) were enriched (Fig. 2 A and B), in accor- ceptor (TLR)-mediated immune responses and is a key regulator dance with their role in maintaining the B-cell phenotype. In of TLR-induced proinflammatory gene expression (12, 13). IRF5 contrast, HRS-specific DHSs (Fig. 1D; C) were enriched in directed HL-specific cytokine expression in cooperation with NF- binding motifs for members of the inducible TF families AP-1, κB and protected HRS cells from cell death. Alone or in combi- NF-κB, STAT, and IRF (Fig. 2 A and B), whereas, as previously nation with NF-κB, IRF5 was capable of inducing gene expression demonstrated (19), TF motifs important for the B-cell program alterations in non-Hodgkin and primary murine splenic B cells that were found with decreased frequency. Mapping the different were reminiscent of those found in HL. Furthermore, we identified binding motifs back to enriched sequences showed their associ- a transcriptional cross-talk between IRF5 and AP-1, as IRF5 di- ation with NH- or HRS-specific DHSs, respectively, and dem- rected the activation of the known abundant and HL-specific AP-1 onstrated that they clustered around the central position of the complex. These data describe a powerful method for the identifi- DHS (SI Appendix, Fig. S2 A–D). Motif distribution was not cation of deregulated TF activities in human lymphoma, which led random, as AP-1, STAT, and IRF motifs showed a preferred to the identification of IRF5 as a key regulator of HRS cell biology.
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