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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, 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.

SUBMITTER: Mallm JP

PROVIDER: S-EPMC6529931 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks.

Mallm Jan-Philipp JP Iskar Murat M Ishaque Naveed N Klett Lara C LC Kugler Sabrina J SJ Muino Jose M JM Teif Vladimir B VB Poos Alexandra M AM Großmann Sebastian S Erdel Fabian F Tavernari Daniele D Koser Sandra D SD Schumacher Sabrina S Brors Benedikt B König Rainer R Remondini Daniel D Vingron Martin M Stilgenbauer Stephan S Lichter Peter P Zapatka Marc M Mertens Daniel D Rippe Karsten K

Molecular systems biology 20190522 5

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 c ...[more]

PMID: 31118277

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Project description:Background:Translocations of the IGH locus on 14q32.3 are present in about 8% of patients with chronic lymphocytic leukemia (CLL) and contribute to leukemogenesis by deregulating the expression of the IGH-partner genes. Identification of these genes and investigation of the downstream effects of their deregulation can reveal disease-causing mechanisms. Case presentation:We report on the molecular characterization of a novel t(12;14)(q23.2;q32.3) in CLL. As a consequence of the rearrangement ASCL1 was brought into proximity of the IGHJ-C? enhancer and was highly overexpressed in the aberrant B-cells of the patient, as shown by qPCR and immunohistochemistry. ASCL1 encodes for a transcription factor acting as a master regulator of neurogenesis, is overexpressed in neuroendocrine tumors and a promising therapeutic target in small cell lung cancer (SCLC). Its overexpression has also been recently reported in acute adult T-cell leukemia/lymphoma.To examine possible downstream effects of the ASCL1 upregulation in CLL, we compared the gene expression of sorted CD5+ cells of the translocation patient to that of CD19+ B-cells from seven healthy donors and detected 176 significantly deregulated genes (Fold Change ?2, FDR p???0.01). Deregulation of 55 genes in our gene set was concordant with at least two studies comparing gene expression of normal and CLL B-lymphocytes. INSM1, a well-established ASCL1 target in the nervous system and SCLC, was the gene with the strongest upregulation (Fold Change?=?209.4, FDR p?=?1.37E-4).INSM1 encodes for a transcriptional repressor with extranuclear functions, implicated in neuroendocrine differentiation and overexpressed in the majority of neuroendocrine tumors. It was previously shown to be induced in CLL cells but not in normal B-cells upon treatment with IL-4 and to be overexpressed in CLL cells with unmutated versus mutated IGHV genes. Its role in CLL is still unexplored. Conclusion:We identified ASCL1 as a novel IGH-partner gene in CLL. The neural transcription factor was strongly overexpressed in the patient's CLL cells. Microarray gene expression analysis revealed the strong upregulation of INSM1, a prominent ASCL1 target, which was previously shown to be induced in CLL cells upon IL-4 treatment. We propose further investigation of the expression and potential role of INSM1 in CLL.

Dataset Information

Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks.

Publications

Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks.

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