High-throughput sequencing reveals a simple model of nucleosome energetics
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ABSTRACT:
PROVIDER: PRJNA130885 | ENA |
REPOSITORIES: ENA
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Project description:We use nucleosome maps obtained by high-throughput sequencing to study sequence specificity of intrinsic histone-DNA interactions. In contrast with previous approaches, we employ an analogy between a classical one-dimensional fluid of finite-size particles in an arbitrary external potential and arrays of DNA-bound histone octamers. We derive an analytical solution to infer free energies of nucleosome formation directly from nucleosome occupancies measured in high-throughput experiments. The sequence-specific part of free energies is then captured by fitting them to a sum of energies assigned to individual nucleotide motifs. We have developed hierarchical models of increasing complexity and spatial resolution, establishing that nucleosome occupancies can be explained by systematic differences in mono- and dinucleotide content between nucleosomal and linker DNA sequences, with periodic dinucleotide distributions and longer sequence motifs playing a secondary role. Furthermore, similar sequence signatures are exhibited by control experiments in which genomic DNA is either sonicated or digested with micrococcal nuclease in the absence of nucleosomes, making it possible that current predictions based on highthroughput nucleosome positioning maps are biased by experimental artifacts.
2010-08-20 | GSE23712 | GEO
Project description:We use nucleosome maps obtained by high-throughput sequencing to study sequence specificity of intrinsic histone-DNA interactions. In contrast with previous approaches, we employ an analogy between a classical one-dimensional fluid of finite-size particles in an arbitrary external potential and arrays of DNA-bound histone octamers. We derive an analytical solution to infer free energies of nucleosome formation directly from nucleosome occupancies measured in high-throughput experiments. The sequence-specific part of free energies is then captured by fitting them to a sum of energies assigned to individual nucleotide motifs. We have developed hierarchical models of increasing complexity and spatial resolution, establishing that nucleosome occupancies can be explained by systematic differences in mono- and dinucleotide content between nucleosomal and linker DNA sequences, with periodic dinucleotide distributions and longer sequence motifs playing a secondary role. Furthermore, similar sequence signatures are exhibited by control experiments in which genomic DNA is either sonicated or digested with micrococcal nuclease in the absence of nucleosomes, making it possible that current predictions based on highthroughput nucleosome positioning maps are biased by experimental artifacts. Included are raw (eland) and mapped (wig) reads. The mapped reads are provided in eland and wiggle formats, and the raw reads are included in the eland file. This series includes only Mnase control data. The sonicated control is part of this already published accession, as is a in vitro nucleosome map: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15188 We also studied data (in vitro and in vivo maps as well as a model) from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13622 and from: http://www.ncbi.nlm.nih.gov/sra/?term=SRA001023
2010-08-20 | E-GEOD-23712 | biostudies-arrayexpress
Project description:We use genome-wide nucleosome maps to study sequence specificity of intrinsic histone-DNA interactions. In contrast with previous approaches, we employ an analogy between a classical one-dimensional fluid of finite-size particles in an arbitrary external potential and arrays of DNA-bound histone octamers. We derive an analytical solution to infer free energies of nucleosome formation directly from nucleosome occupancies measured in high-throughput experiments. The sequence-specific part of free energies is then captured by fitting them to a sum of energies assigned to individual nucleotide motifs. We have developed hierarchical models of increasing complexity and spatial resolution, establishing that nucleosome occupancies can be explained by systematic differences in mono- and dinucleotide content between nucleosomal and linker DNA sequences, with periodic dinucleotide distributions and longer sequence motifs playing a minor role. Furthermore, similar sequence signatures are exhibited by control experiments in which nucleosome-free genomic DNA is either sonicated or digested with micrococcal nuclease, making it possible that current predictions based on high-throughput nucleosome-positioning maps are biased by experimental artifacts.
| S-EPMC3000311 | biostudies-literature
Project description:activated sludge simple Raw sequence reads
| PRJNA825387 | ENA
Project description:Understanding how chromatin structure affects cellular functions such as transcription and replication in human cells has been limited by a lack of sufficient nucleosome positioning data. We describe a high-resolution microarray approach combined with a novel analysis algorithm to examine the translational nucleosome positions in 3,692 promoters within seven human cell lines. Unlike unexpressed genes without transcription pre-initiation complexes at their promoters, expressed genes or genes containing pre-initiation complexes exhibit characteristic nucleosome-free regions at their transcription start sites. Coupling these data to ChIP-chip analyses reveals that the melanocyte master transcriptional regulator MITF binds predominantly to nucleosome-free regions, supporting the model that nucleosomes limit sequence accessibility. This study thus presents the first global view of human nucleosome positioning and provides a high-throughput tool for analyzing chromatin structure in development and disease. Keywords: Nucleosome positions, MNase digestion, cell type comparison
2007-01-15 | GSE6385 | GEO
Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
2022-07-17 | GSE180313 | GEO
Project description:Interventions: Case series:Nucleosome Complex CAR-T cells
Primary outcome(s): Tumor markers
Study Design: Sequential
| 2684952 | ecrin-mdr-crc
Project description:Nuclear proteins bind chromatin to execute and regulate genome-templated processes. While structural and biochemical studies of individual nucleosome interactions have suggested that an acidic patch on the nucleosome disk surface may be a common site for recruitment to chromatin, the pervasiveness of acidic patch binding and whether other nucleosome surface binding hot-spots exist remains unclear. Here, we use nucleosome affinity proteomics with a library of nucleosomes that collectively disrupts all exposed histone surfaces to establish the universal principles of nucleosome binding. We find that the acidic patch and two adjacent surfaces are the primary hot-spots for nucleosome disk binding and are critical for the majority of nucleosome-protein interactions. In contrast, nearly half of the nucleosome disk surface participates only minimally in protein binding. In addition to establishing the fundamental principles of chromatin binding, our screen defines nucleosome surface requirements of nearly 300 nucleosome interacting proteins implicated in diverse nuclear processes including transcription, DNA damage repair, cell cycle regulation, and nuclear architecture. Building from our screen, we demonstrate that the Anaphase-Promoting Complex/Cyclosome directly binds the acidic patch and elucidate a redundant charge-based mechanism of acidic patch binding by nuclear pore protein ELYS. Overall, our interactome screen illuminates a highly competitive nucleosome binding hub for chromatin-targeted activities and curates a list of nucleosome interacting proteins that will enable mechanistic exploration of many unexpected chromatin-templated nuclear processes.
2020-06-24 | PXD018690 | Pride
Project description:The energetics and physiological impact of cohesin extrusion
| PRJNA384026 | ENA