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Linking the epigenetic landscape in chronic lymphocytic leukemia to deregulated chromatin networks

ABSTRACT: Aberrant chromatin features and epigenetic signaling emerge as an important part of the tumor disease state in chronic lymphocytic leukemia (CLL). However, an integrative analysis of the malignant chromatin landscape is currently missing. Here, we mapped DNA-methylation, nucleosome position, 7 histone modifications, ATAC-seq and the transcriptome in primary CD19+ sorted B-cells from the peripheral blood of CLL patients in comparison to non-malignant lymphocytes of healthy donor reference samples. On the > 50 kb scale we identified global differences with respect to DNA methylation, nucleosome positioning and histone modifications in CLL. Furthermore, a chromatin state annotation was developed to identify deregulated chromatin features of promoters and enhancers in CLL. By integrating these findings with an ATAC-seq based transcription factor binding analysis we identified a set of promoters and enhancers specific to CLL that were enriched in certain transcription factors binding motifs and genes of the BCR signaling pathway. Thus, our study provides an in-depth map of the CLL chromatin landscape and links chromatin state changes at promoters and enhancers to deregulated pathways.

PROVIDER: EGAS00001002518 | EGA |

REPOSITORIES: EGA

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

Project description: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, 7 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. Mallm JP, Iskar M, Ishaque N, Klett LC, Kugler SJ, Muino JM, Teif VB, Poos AM, Großmann S, Erdel F, Tavernari D, Koser SD, Schumacher S, Brors B, König R, Remondini D, Vingron M, Stilgenbauer S, Lichter P, Zapatka M, Mertens D & Rippe K (2019) Linking aberrant chromatin features in chronic lymphocytic leukemia to deregulated transcription factor networks. Mol Syst Biol 15, e8339. doi: 10.15252/msb.20188339

2019-05-22 | GSE113336 | GEO

MARCS: Modification Atlas for Regulation by Chromatin States

Project description:Goal of this project was the identification of chromatin interacting proteins whose binding is differentially regulated by various combinatorial chromatin modifications found in different chromatin states such as promoters, enhancers and heterochromatin. To achieve this, recombinant modified nucleosomes representing different chromatin states were assembled from canonical histones, H2A.Z and modified ligated H3/H4 histone proteins and biotinylated nucleosomal DNAs. Assembled nucleosomes were immobilized on streptavidin-coated beads via biotinylated di-nucleosomal 601 DNA and used for nucleosome affinity purifications to identify proteins regulated by chromatin modifications from SILAC-labelled HeLaS3 nuclear extracts (Arg10 and Lys8). SILAC affinity purifications were carried out in "forward" (heavy extract on modified nucleosome and light extract on unmodified nucleosome) and "reverse" (light extract on modified nucleosome and heavy extract on unmodified nucleosome) label-swap experiments and protein abundances were quantified by MaxQuant. Initial trial experiments with biotinylated mono-, di- and tetra- 601 nucleosomes are also deposited along with the data for the di-nucleosome experiments. See also: Bartke et al., 2010. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143, 470–484; doi:10.1016/j.cell.2010.10.012. The H4K20me2 samples from this experiment were previously deposited with identifier PXD009281. These were published in: Nakamura et al., 2019. H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature Cell Biology 21, 311–318; doi: 10.1038/s41556-019-0282-9.

2023-12-12 | PXD018966 | Pride

Pull-down affinity purifications using di-nucleosomes decorated with enhancer-associated modifications and incorporating 200bp linker DNA

2023-12-12 | PXD041443 | Pride

Dissecting the effect of a long linker DNA on protein binding to di-nucleosomes decorated with promoter-associated PTMs

Project description:Characteristic features of chromatin states are not limited to particular epigenetic modifications but include other regulatory cues, such as linker DNA length, typically ranging from around 35-55 bp in most eu- and heterochromatin domains (Valouev et al, 2011; Voong et al., 2016, Cell) to over 200 bp in nucleosome-depleted regions (NDRs) found at active enhancers and promoters (Schones et al, 2008; Hansen He et al, 2010). To investigate whether and how the nucleosome linker DNA affects chromatin recognition by nuclear proteins we performed a set of affinity purifications using di-nucleosomes incorporating different DNA linkers. Here, we investigated the effect of a 200 bp di-nucleosome linker DNA represented by scrambled DNA or SV40 promoter DNA sequence on the nuclear protein binding to di-nucleosome decorated with promoter-associated modifications, including H3K4me3K9acK14acK18acK23acK27ac, H4K5acK8acK12acK16acK20me2 and histone variant H2A.Z Below is a description (modifications and linker) of di-nucleosomes used in pull-downs with HeLa nuclear extracts followed by label-free MS: 1. H3K4me3-5ac,H4K20me2-4ac, H2AZ, 50bp linker 2. H3K4me3-5ac,H4K20me2-4ac, H2AZ, 200bp scrambled DNA linker 3. H3K4me3-5ac,H4K20me2-4ac, H2AZ, 200bp SV40 promoter DNA linker 4. Unmod. H3&H4, 50bp linker 5. Unmod. H3&H4, 200bp scrambled DNA linker 6. Unmod. H3&H4, 200bp SV40 promoter DNA linker

2023-12-10 | PXD041835 | Pride

Hypersensitive Nucleosomes in Chromatin Are Intrinsic to the Structure of Active, Tissue-Specific Enhancers [MNase-Seq]

Project description:In higher eukaryotes, enhancers and promoters share many properties, including binding of transcription factors, existing in open chromatin, and bidirectional transcription. Yet the structural features that distinguish enhancers and promoters are unclear. Genome-wide micrococcal nuclease (MNase) studies previously interpreted MNase hypersensitivity to indicate that active enhancers and promoters are nucleosome-free, yet other studies found histone variants and post-translational modifications at active enhancers. We find that prior MNase genomic studies have an overdigestion bias and that low-level MNase digestion, coupled with mapping core histones, reveals two classes of MNase-hypersensitive sites: at active promoters, which are nucleosome depleted, and at tissue-specific enhancers, which retain core histones and co-bound transcription factors substantially more than promoters. Hypersensitivity of active enhancer nucleosomes may reflect their preferential exposure in chromatin and can be maintained by pioneer transcription factors such as FoxA. These findings unveil fundamental differences in the chromatin structure of active enhancers and promoters.

2016-04-08 | GSE57558 | GEO

Hypersensitive Nucleosomes in Chromatin Are Intrinsic to the Structure of Active, Tissue-Specific Enhancers [ChIP-Seq]

2016-04-08 | GSE57557 | GEO

Hypersensitive Nucleosomes in Chromatin Are Intrinsic to the Structure of Active, Tissue-Specific Enhancers [ChIP-exo]

2016-04-08 | GSE57556 | GEO

Genome-wide nucleosome dynamics in glucocorticoid-treated acute lymphoblastic leukemia cell line, RS4;11

Project description:Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia. For the first time, we demonstrate functionally distinct modes of nucleosome remodeling upon chromatin binding by GR, which we term central, non-central, phased, and minimal. Central and non-central remodeling reflect nucleosome eviction by GR and cofactors, respectively. Phased remodeling involves nucleosome repositioning and is associated with rapidly activated enhancers and induction of gene expression. Minimal remodeling sites initially have low levels of enhancerassociated histone modification, but the majority of these regions gain H3K4me2 or H3K27Ac to become de novo enhancers. Minimal remodeling regions are associated with gene ontologies specific to decreased B cell number and mTOR inhibition and may make unique contributions to glucocorticoid-induced leukemia cell death. Our findings form a novel framework for understanding the dynamic interplay between transcription factor binding, nucleosome remodeling, enhancer function, and gene expression in the leukemia response to glucocorticoids.

2015-10-01 | GSE71616 | GEO

Histone acetylation H2BK20ac marks cell-state specific active regulatory elements

Project description:Characterisation of different histone modifications is crucial to understand gene regulation. In order to study the most predictive histone modification for active enhancers we created unbiased set of enhancers and used machine learning approach. Our approach revealed an unconventional histone modification H2BK20ac as most efficient marker of active enhancers. H2BK20ac also showed superior coverage of tissue specific active enhancers in complex invivo samples. Adding H2BK20ac to set of conventional histone modifications lead to identification of new chromatin state which could be active enhancers. H2BK20ac tends to occur only at cell-type specific active promoters and showed higher specificity for related disease mutations than H3K27ac and other histone modifications. Using transient state of BV2 microglia cells after lipopolysaccharide based activation, we found that H2BK20ac also marks cell-state specific cis-regulatory elements. Further analysis using inhibition of TGF-beta pathway in BV2 cells and LPS stimulation, revealed differential patterns of H2BK20ac and H3K27ac at genome locations associated with opposite roles response to stmulation. Our study about H2BK20ac hints about a new mechanism of regulation of cell-type specificity and a distinct mode of action of pathways to maintain balance between cell-responses. Chip-seq of H2BK20ac and other histone modifcation was performed in 3 cell types and embryonic mouse forebrain. The sensitivity for active enhancers was compared for different histone modification ChIP-seq.The level of H2BK20ac at promoters and enhancers was assesed for relationship to cell-type specific expression. H2BK20ac signals were also analysed during cell-state transition when microgila are stimulated by LPS

2016-02-25 | E-GEOD-72886 | biostudies-arrayexpress

Nucleosome free DNA- and acetyl histone-binding components recruit SWR1 to yeast promoters for H2A.Z replacement

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2013-09-16 | E-GEOD-49183 | biostudies-arrayexpress

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