Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks
Abstract In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromat...
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-05-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20188339 |
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| author | Jan‐Philipp Mallm Murat Iskar Naveed Ishaque Lara C Klett Sabrina J Kugler Jose M Muino Vladimir B Teif Alexandra M Poos Sebastian Großmann Fabian Erdel Daniele Tavernari Sandra D Koser Sabrina Schumacher Benedikt Brors Rainer König Daniel Remondini Martin Vingron Stephan Stilgenbauer Peter Lichter Marc Zapatka Daniel Mertens Karsten Rippe |
| author_facet | Jan‐Philipp Mallm Murat Iskar Naveed Ishaque Lara C Klett Sabrina J Kugler Jose M Muino Vladimir B Teif Alexandra M Poos Sebastian Großmann Fabian Erdel Daniele Tavernari Sandra D Koser Sabrina Schumacher Benedikt Brors Rainer König Daniel Remondini Martin Vingron Stephan Stilgenbauer Peter Lichter Marc Zapatka Daniel Mertens Karsten Rippe |
| author_sort | Jan‐Philipp Mallm |
| collection | DOAJ |
| description | Abstract In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF, as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF. CLL samples displayed a H3K4me3 redistribution and nucleosome gain at promoters as well as changes of enhancer activity and enhancer linkage to target genes. A DNA binding motif analysis identified transcription factors that gained or lost binding in CLL at sites with aberrant chromatin features. These findings were integrated into a gene regulatory enhancer containing network enriched for B‐cell receptor signaling pathway components. Our study predicts novel molecular links to targets of CLL therapies and provides a valuable resource for further studies on the epigenetic contribution to the disease. |
| format | Article |
| id | doaj-art-d531e1d3965044bc9b7dc0b0a7049c9a |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2019-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-d531e1d3965044bc9b7dc0b0a7049c9a2025-08-20T03:46:37ZengSpringer NatureMolecular Systems Biology1744-42922019-05-0115512010.15252/msb.20188339Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networksJan‐Philipp Mallm0Murat Iskar1Naveed Ishaque2Lara C Klett3Sabrina J Kugler4Jose M Muino5Vladimir B Teif6Alexandra M Poos7Sebastian Großmann8Fabian Erdel9Daniele Tavernari10Sandra D Koser11Sabrina Schumacher12Benedikt Brors13Rainer König14Daniel Remondini15Martin Vingron16Stephan Stilgenbauer17Peter Lichter18Marc Zapatka19Daniel Mertens20Karsten Rippe21Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Theoretical Bioinformatics and Heidelberg Center for Personalized Oncology, German Cancer Research Center (DKFZ)Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantMechanisms of Leukemogenesis, German Cancer Research Center (DKFZ)Department of Computational Molecular Biology, Max Planck Institute for Molecular GeneticsSchool of Biological Sciences, University of EssexDivision of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ)Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ)Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University HospitalDepartment of Physics and Astronomy, Bologna UniversityDepartment of Computational Molecular Biology, Max Planck Institute for Molecular GeneticsDepartment of Internal Medicine III, University Hospital UlmDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ)Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioquantAbstract In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF, as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF. CLL samples displayed a H3K4me3 redistribution and nucleosome gain at promoters as well as changes of enhancer activity and enhancer linkage to target genes. A DNA binding motif analysis identified transcription factors that gained or lost binding in CLL at sites with aberrant chromatin features. These findings were integrated into a gene regulatory enhancer containing network enriched for B‐cell receptor signaling pathway components. Our study predicts novel molecular links to targets of CLL therapies and provides a valuable resource for further studies on the epigenetic contribution to the disease.https://doi.org/10.15252/msb.20188339bivalent promoterDNA methylationenhancergene regulatory networkshistone modifications |
| spellingShingle | Jan‐Philipp Mallm Murat Iskar Naveed Ishaque Lara C Klett Sabrina J Kugler Jose M Muino Vladimir B Teif Alexandra M Poos Sebastian Großmann Fabian Erdel Daniele Tavernari Sandra D Koser Sabrina Schumacher Benedikt Brors Rainer König Daniel Remondini Martin Vingron Stephan Stilgenbauer Peter Lichter Marc Zapatka Daniel Mertens Karsten Rippe Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks Molecular Systems Biology bivalent promoter DNA methylation enhancer gene regulatory networks histone modifications |
| title | Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| title_full | Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| title_fullStr | Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| title_full_unstemmed | Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| title_short | Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| title_sort | linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks |
| topic | bivalent promoter DNA methylation enhancer gene regulatory networks histone modifications |
| url | https://doi.org/10.15252/msb.20188339 |
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