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Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma

Item Type:Article
Title:Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma
Creators Name:Kreher, S., Bouhlel, M.A., Cauchy, P., Lamprecht, B., Li, S., Grau, M., Hummel, F., Köchert, K., Anagnostopoulos, I., Jöhrens, K., Hummel, M., Hiscott, J., Wenzel, S.S., Lenz, P., Schneider, M., Küppers, R., Scheidereit, C., Giefing, M., Siebert, R., Rajewsky, K., Lenz, G., Cockerill, P.N., Janz, M., Dörken, B., Bonifer, C. and Mathas, S.
Abstract:Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered 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 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-{kappa}B to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.
Keywords:Amino Acid Motifs, B-Lymphocytes, Cell Lineage, Chemokines, Chemotaxis, Chromatin, Cytokines, Deoxyribonuclease I, Gene Expression Profiling, Hodgkin Disease, Inflammation, Interferon Regulatory Factors, Lymphoma, Mononuclear Leukocytes, Neoplastic Gene Expression Regulation, Non-Hodgkin Lymphoma, NF-{kappa} B, Oligonucleotide Array Sequence Analysis, Plasmids, Spleen, Transcription Factor AP-1, Tumor Cell Line, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:E4513-E4522
Date:21 October 2014
Official Publication:https://doi.org/10.1073/pnas.1406985111
PubMed:View item in PubMed

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