Nucleosome repositioning in chronic lymphocytic leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158745 | GEO | 2023/08/27
REPOSITORIES: GEO
Similar Datasets
Project description:The nature of chromatin as regular succession of nucleosomes has gained iconic status. However, since most nucleosomes in metazoans are poorly positioned it is unknown to which extent the bulk genomic nucleosome repeat length (NRL) reflects the regularity and spacing of nucleosome arrays at individual loci. We describe a new approach to map nucleosome fiber regularity and spacing through sequencing oligonucleosome-derived DNA by classical as well as emergent nanopore-technology. This revealed modulation of chromatin regularity and NRL depending on functional chromatin states independently of nucleosome positioning and even in unmappable regions. We also found that that nucleosome arrays downstream of silent promoters are considerably more regular than those downstream of highly expressed ones, despite most extensive nucleosome phasing of the latter. Our approach is generally applicable and provides an important parameter of chromatin organisation that so far had been missing.
2018-02-20 | GSE110807 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we found widespread heterogeneity in the CLL chromatin landscape, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research.
2016-06-26 | GSE81274 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status â which distinguishes the two major subtypes of CLL â was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we found widespread heterogeneity in the CLL chromatin landscape, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research. Genome-wide profiling of chromatin states and gene expression levels in 88 CLL samples from 55 individuals gave rise to 88 ATAC-seq profiles, 40 ChIPmentation profiles (10 samples, each with 3 different antibodies and matched immunoglobulin control), and 10 RNA-seq profiles. Raw sequence data has been deposited at the EBI's European Genome-phenome Archive (EGA) under the accession number EGAS00001001821 (controlled access to protect patient privacy).
2016-06-26 | E-GEOD-81274 | biostudies-arrayexpress
Project description:Knowing the exact positions of nucleosomes not only advances our understanding of their role in gene regulation, but also the mechanisms that underlie between-species variation in chromatin structure. We have generated a chemical map of nucleosomes in vivo in Schizosaccharomyces pombe at base pair resolution. This new map reveals that S.pombe genome shares a similar periodic linker length distribution with Saccharomyces cerevisiae, but with major distinctions in nucleosomal/linker DNA sequence features. In S.pombe, A/T rich sequences are enriched in the nucleosome core region, particularly +/-20 bp of dyad, while they are disfavored in S.cerevisiae nucleosomes. The poly (dA-dT) tracts only slightly affect the nucleosome occupancy in S.pombe; and they possess preferential rotational positions within the nucleosome core with significant enrichment in the 10-30 bp region from the dyad for longer tracts. S.pombe does not have well-defined nucleosome free region immediately upstream of most transcription start sites (TSS), instead the -1 nucleosome is positioned with regular distance to the +1 nucleosome, and its occupancy is negatively correlated with gene expression. The nucleosomes around TSS show more pronounced bidirectional phasing when the intergenic distance is relatively short, and the downstream nucleosome positioning is strongly correlated with DNA sequence features. We discovered that heterochromatin regions tend to have sparse nucleosome positioning, mixed with both well-positioned and fuzzy nucleosomes. The S.pombe map suggests that some of nucleosome positioning codes, formerly thought to be intrinsic, may largely depend on species-specific extrinsic factors including linker histone, chromatin remodelers and other DNA-binding proteins. 2 samples were analyzed with high throughput paired-end parallel sequencing. Both samples were created using the same chemical mapping protocol
2013-11-12 | E-GEOD-46975 | biostudies-arrayexpress
Project description:DNA methylation and nucleosome positioning work together to generate chromatin structures that regulate gene expression. Nucleosomes are typically mapped using nuclease digestion requiring significant amounts of material and varying enzyme concentrations. We have developed a method (NOMe-seq) that uses a GpC methyltransferase (M.CviPI) and next generation sequencing to generate a high resolution footprint of nucleosome positioning genome-wide using less than 1 million cells while retaining endogenous DNA methylation information from the same DNA strand. Using a novel bioinformatics pipeline we show a striking anti-correlation between nucleosome occupancy and DNA methylation at CTCF regions, that is not present at promoters. We further show that the extent of nucleosome depletion at promoters is directly correlated to expression level and can accommodate multiple nucleosomes and provide genome-wide evidence that expressed non-CpG island promoters are nucleosome depleted. Importantly, NOMe-seq obtains DNA methylation and nucleosome positioning information from the same DNA molecule, giving the first genome-wide DNA methylation and nucleosome positioning correlation at the single molecule and thus, single cell level that can be used to monitor disease progression and response to therapy. Nucleosome Occupancy and Methylome-Sequencing (NOMe-Seq) on IMR90 cell line and 2 GBM cell lines
2012-09-12 | E-GEOD-40770 | biostudies-arrayexpress
Project description:Knowing the exact positions of nucleosomes not only advances our understanding of their role in gene regulation, but also the mechanisms that underlie between-species variation in chromatin structure. We have generated a chemical map of nucleosomes in vivo in Schizosaccharomyces pombe at base pair resolution. This new map reveals that S.pombe genome shares a similar periodic linker length distribution with Saccharomyces cerevisiae, but with major distinctions in nucleosomal/linker DNA sequence features. In S.pombe, A/T rich sequences are enriched in the nucleosome core region, particularly +/-20 bp of dyad, while they are disfavored in S.cerevisiae nucleosomes. The poly (dA-dT) tracts only slightly affect the nucleosome occupancy in S.pombe; and they possess preferential rotational positions within the nucleosome core with significant enrichment in the 10-30 bp region from the dyad for longer tracts. S.pombe does not have well-defined nucleosome free region immediately upstream of most transcription start sites (TSS), instead the -1 nucleosome is positioned with regular distance to the +1 nucleosome, and its occupancy is negatively correlated with gene expression. The nucleosomes around TSS show more pronounced bidirectional phasing when the intergenic distance is relatively short, and the downstream nucleosome positioning is strongly correlated with DNA sequence features. We discovered that heterochromatin regions tend to have sparse nucleosome positioning, mixed with both well-positioned and fuzzy nucleosomes. The S.pombe map suggests that some of nucleosome positioning codes, formerly thought to be intrinsic, may largely depend on species-specific extrinsic factors including linker histone, chromatin remodelers and other DNA-binding proteins.
2013-11-12 | GSE46975 | GEO
Project description:Nucleosomes are important for gene regulation because their arrangement on the genome can control which proteins bind to DNA. Currently, few human nucleosomes are thought to be consistently positioned across cells; however, this has been difficult to assess due to the limited resolution of existing data. We performed paired-end sequencing of micrococcal nuclease-digested chromatin (MNase-seq) from seven lymphoblastoid cell lines and mapped over 3.6 billion MNase-seq fragments to the human genome to create the highest-resolution map of nucleosome occupancy to date in a human cell type. In contrast to previous results, we find that most nucleosomes have more consistent positioning than expected by chance and a substantial fraction (8.7%) of nucleosomes have moderate to strong positioning. In aggregate, nucleosome sequences have 10 bp periodic patterns in dinucleotide frequency and DNase I sensitivity; and, across cells, nucleosomes frequently have translational offsets that are multiples of 10 bp. We estimate that almost half of the genome contains regularly spaced arrays of nucleosomes, which are enriched in active chromatin domains. Single nucleotide polymorphisms that reduce DNase I sensitivity can disrupt the phasing of nucleosome arrays, which indicates that they often result from positioning against a barrier formed by other proteins. However, nucleosome arrays can also be created by DNA sequence alone. The most striking example is an array of over 400 nucleosomes on chromosome 12 that is created by tandem repetition of sequences with strong positioning properties. In summary, a large fraction of nucleosomes are consistently positioned-in some regions because they adopt favored sequence positions, and in other regions because they are forced into specific arrangements by chromatin remodeling or DNA binding proteins. MNase-seq of 7 human lymphoblastoid cell lines from the HapMap project
2012-08-01 | E-GEOD-36979 | biostudies-arrayexpress
Project description:Positioning of nucleosomes along DNA is an integral regulator of chromatin accessibility and gene expression in diverse cell types. However, the precise nature of how post-translational modification of histones such as activating trimethylated histone 3 lysine 4 (H3K4me3), or histone demethylases including the H3K4 demethylase, KDM5B, impacts nucleosome positioning around transcriptional start sites (TSS) of active genes is poorly understood. Here, we report that KDM5B is a critical regulator of nucleosome positioning in embryonic stem (ES) cells. Micrococcal nuclease sequencing (MNase-Seq) revealed increased enrichment of nucleosomes around TSS regions and DNase I hypersensitive sites in KDM5B-depleted ES cells. Moreover, depletion of KDM5B resulted in a widespread redistribution and disorganization of nucleosomes in a sequence-dependent manner. Dysregulated nucleosome phasing was also evident in KDM5B-depleted ES cells, including asynchronous nucleosome spacing surrounding TSS regions, where nucleosome variance was positively correlated with the degree of asynchronous phasing. The redistribution of nucleosomes around TSS regions in KDM5B-depleted ES cells is correlated with dysregulated gene expression, and altered H3K4me3 and RNA polymerase II occupancy. In addition, we found that DNA shape features varied significantly at regions with shifted nucleosomes. Altogether, our data support a role for KDM5B in regulating nucleosome positioning in ES cells.
2019-04-23 | GSE123249 | GEO
Project description:Cell differentiation is associated with changes in chromatin organization and gene expression. In this study, we examine chromatin structure following differentiation of the human myeloid leukemia cell line (HL-60/S4) into granulocytes with retinoic acid (RA) or into macrophage with phorbol ester (TPA). We performed ChIP-seq of histone H3 and its modifications, analyzing changes in nucleosome occupancy, nucleosome repeat length, eu-/heterochromatin redistribution and properties of epichromatin (surface chromatin adjacent to the nuclear envelope). Nucleosome positions changed genome-wide, exhibiting a specific class of alterations involving nucleosome loss in extended (~1kb) regions, pronounced in enhancers and promoters. Genes that lost nucleosomes at their promoters showed a tendency to be upregulated. On the other hand, nucleosome gain was not systematic at functional elements and did not show simple effects on transcript levels. The average genome-wide nucleosome repeat length (NRL) did not change significantly with differentiation. However, we detected an approximate 10 bp NRL decrease around the hematopoietic transcription factor (TF) PU.1 and the architectural protein CTCF, suggesting an effect on NRL proximal to TF binding sites. Nucleosome occupancy changed in regions associated with H3K4me3 in differentiated cells, compared to untreated HL-60/S4 cells. Epichromatin regions, largely unaffected by cell differentiation, revealed an increased GC content and high nucleosome density compared to surrounding chromatin. Epichromatin showed depletion of major (permissive and repressive) histone modifications and revealed enrichment with PML body-associated genes. In general, chromatin changes during HL-60/S4 differentiation appeared to be more localized, compared to changes among diverse cell types studied elsewhere, suggesting that the cell lineage differentiation of HL-60/S4 cells involves less drastic nucleosome repositioning.
2017-04-27 | GSE90992 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a biologically and clinically heterogeneous disease. The somatic hypermutation status of the immunoglobulin heavy chain variable (IGHV) genes has been identified as one of the most robust prognostic markers in CLL. Patients with unmutated IGHV status (U-CLL) typically experience an inferior outcome compared to those whose clones express mutated IGHV genes (M-CLL). We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from a group of 43 CLL patients using reduced representation bisulfite sequencing (RRBS). Using base-pair resolution methylation sequencing, 2323 differentially methylated regions between CLL and normal B-cells (CLL-specific DMRs) and 569 between M-CLL and U-CLL samples (IGHV-specific DMRs) were identified in the CLL genomes. The IGHV-specific DMRs are mostly unique when compared to the CLL-specific DMRs. Less than 10% of the IGHV-specific DMRs are located in promoter regions; however, more than half of these overlap with known DNase I hypersensitive sites, enhancer regions marked by histone modification (H3K4Me1 and H3K27Ac), and transcription factor binding sites in the ENCODE datasets, which indicates that these DMRs contain regulatory sequences. Distinctive DNA methylation patterns were observed in M-CLL and U-CLL samples. Overall, U-CLL was found to contain 50% more hypermethylated regions than M-CLL samples. The hypermethylated loci observed in the U-CLL samples also appear to be hypermethylated in normal naïve B-cells as compared memory B-cells, suggesting that M-CLL and U-CLL differ in differentiation status corresponding to normal B-cell differentiation stages. RNA-seq analysis performed using matched samples (n=34), in which both DNA methylation and gene expression data were available, demonstrated excellent correlation between DNA methylation and gene expression. Several genes whose expression status was previously shown to be associated with CLL prognosis such as ZAP70, CRY1, LDOC1, SEPT10, LAG3, and LPL were differentially methylated in the promoter regions between M-CLL and U-CLL samples indicating that DNA methylation plays an important role in defining the gene expression patterns of these prognostic genes. We further validated 9 genes with IGHV-specific DMRs in the promoter regions using bisulfite pyrosequencing, and the results demonstrated excellent correlation between differential methylation and IGHV mutation status. These novel differentially methylated genes could be developed into biomarkers for CLL prognosis. In addition, DNA hypomethylation was observed in a significant number of genes involved in lymphocyte activation such as PDCD1, NFAT1, and CD5. DNA hypomethylation was observed in the proximal promoter and far up-stream enhancer regions of CD5, an important cell surface marker that uniquely identifies CLL. Overall, the DNA methylation landscape in CLL patients indicates that CLL B cells possess an active B-cell phenotype; at the same time, U-CLL and M-CLL are faithfully committed to their lineage resembling either naïve or memory B-cells. In summary, this comprehensive DNA methylation analysis has identified a large number of novel epigenetic changes in CLL patients. The results from this study will further advance our understanding of the epigenetic contribution to molecular subtypes in CLL. To perform a transcriptome analysis in CLL, we generated sequencing libraries from total RNA isolated from purified B-cells of CLL patients and healthy donnors. The RNA-seq libraries were sequenced using Illumina HiSeq2000 sequencer with a read length of 100bp. 11 CLL B-cell samples, 3 normal control samples including one each of normal CD19+ B cells were studied. We generated 20-30 million Illumina sequencing reads for each sample.
2015-02-21 | E-GEOD-66117 | biostudies-arrayexpress