Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Local DNA topography correlates with functional noncoding regions of the human genome.

ABSTRACT: The three-dimensional molecular structure of DNA, specifically the shape of the backbone and grooves of genomic DNA, can be dramatically affected by nucleotide changes, which can cause differences in protein-binding affinity and phenotype. We developed an algorithm to measure constraint on the basis of similarity of DNA topography among multiple species, using hydroxyl radical cleavage patterns to interrogate the solvent-accessible surface area of DNA. This algorithm found that 12% of bases in the human genome are evolutionarily constrained-double the number detected by nucleotide sequence-based algorithms. Topography-informed constrained regions correlated with functional noncoding elements, including enhancers, better than did regions identified solely on the basis of nucleotide sequence. These results support the idea that the molecular shape of DNA is under selection and can identify evolutionary history.

SUBMITTER: Parker SC

PROVIDER: S-EPMC2749491 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Local DNA topography correlates with functional noncoding regions of the human genome.

Parker Stephen C J SC Hansen Loren L Abaan Hatice Ozel HO Tullius Thomas D TD Margulies Elliott H EH

Science (New York, N.Y.) 20090312 5925

The three-dimensional molecular structure of DNA, specifically the shape of the backbone and grooves of genomic DNA, can be dramatically affected by nucleotide changes, which can cause differences in protein-binding affinity and phenotype. We developed an algorithm to measure constraint on the basis of similarity of DNA topography among multiple species, using hydroxyl radical cleavage patterns to interrogate the solvent-accessible surface area of DNA. This algorithm found that 12% of bases in t ...[more]

PMID: 19286520

Similar Datasets

Oxytocin modulates local topography of human functional connectome in healthy men at rest.

Project description:Oxytocin has recently received remarkable attention for its role as a modulator of human behaviour. Here, we aimed to expand our knowledge of the neural circuits engaged by oxytocin by investigating the effects of intranasal and intravenous oxytocin on the functional connectome at rest in 16 healthy men. Oxytocin modulates the functional connectome within discrete neural systems, but does not affect the global capacity for information transfer. These local effects encompass key hubs of the oxytocin system (e.g. amygdala) but also regions overlooked in previous hypothesis-driven research (i.e. the visual circuits, temporal lobe and cerebellum). Increases in levels of oxytocin in systemic circulation induce broad effects on the functional connectome, yet we provide indirect evidence supporting the involvement of nose-to-brain pathways in at least some of the observed changes after intranasal oxytocin. Together, our results suggest that oxytocin effects on human behaviour entail modulation of multiple levels of brain processing distributed across different systems.

| S-EPMC7811009 | biostudies-literature

Structure Validation of G-Rich RNAs in Noncoding Regions of the Human Genome.

Project description:We present the rapid biophysical characterization of six previously reported putative G-quadruplex-forming RNAs from the 5'-untranslated region (5'-UTR) of silvestrol-sensitive transcripts for investigation of their secondary structures. By NMR and CD spectroscopic analysis, we found that only a single sequence-[AGG]2 [CGG]2 C-folds into a single well-defined G-quadruplex structure. Sequences with longer poly-G strands form unspecific aggregates, whereas CGG-repeat-containing sequences exhibit a temperature-dependent equilibrium between a hairpin and a G-quadruplex structure. The applied experimental strategy is fast and provides robust readout for G-quadruplex-forming capacities of RNA oligomers.

| S-EPMC7318348 | biostudies-literature

Functional topography of the thalamocortical system in human.

Project description:Various studies have indicated that the thalamus is involved in controlling both cortico-cortical information flow and cortical communication with the rest of the brain. Detailed anatomy and functional connectivity patterns of the thalamocortical system are essential to understanding the cortical organization and pathophysiology of a wide range of thalamus-related neurological and neuropsychiatric diseases. The current study used resting-state fMRI to investigate the topography of the human thalamocortical system from a functional perspective. The thalamus-related cortical networks were identified by performing independent component analysis on voxel-based thalamic functional connectivity maps across a large group of subjects. The resulting functional brain networks were very similar to well-established resting-state network maps. Using these brain network components in a spatial regression model with each thalamic voxel's functional connectivity map, we localized the thalamic subdivisions related to each brain network. For instance, the medial dorsal nucleus was shown to be associated with the default mode, the bilateral executive, the medial visual networks; and the pulvinar nucleus was involved in both the dorsal attention and the visual networks. These results revealed that a single nucleus may have functional connections with multiple cortical regions or even multiple functional networks, and may be potentially related to the function of mediation or modulation of multiple cortical networks. This observed organization of thalamocortical system provided a reference for studying the functions of thalamic sub-regions. The importance of intrinsic connectivity-based mapping of the thalamocortical relationship is discussed, as well as the applicability of the approach for future studies.

| S-EPMC6363530 | biostudies-literature

Defining functional DNA elements in the human genome.

Project description:With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

| S-EPMC4035993 | biostudies-literature

Comparative annotation of functional regions in the human genome using epigenomic data.

Project description:Epigenetic regulation is dynamic and cell-type dependent. The recently available epigenomic data in multiple cell types provide an unprecedented opportunity for a comparative study of epigenetic landscape. We developed a machine-learning method called ChroModule to annotate the epigenetic states in eight ENCyclopedia Of DNA Elements cell types. The trained model successfully captured the characteristic histone-modification patterns associated with regulatory elements, such as promoters and enhancers, and showed superior performance on identifying enhancers compared with the state-of-art methods. In addition, given the fixed number of epigenetic states in the model, ChroModule allows straightforward illustration of epigenetic variability in multiple cell types. Using this feature, we found that invariable and variable epigenetic states across cell types correspond to housekeeping functions and stimulus response, respectively. Especially, we observed that enhancers, but not the other regulatory elements, dictate cell specificity, as similar cell types share common enhancers, and cell-type-specific enhancers are often bound by transcription factors playing critical roles in that cell type. More interestingly, we found some genomic regions are dormant in cell type but primed to become active in other cell types. These observations highlight the usefulness of ChroModule in comparative analysis and interpretation of multiple epigenomes.

| S-EPMC3632130 | biostudies-literature

A novel method for discovering local spatial clusters of genomic regions with functional relationships from DNA contact maps.

Project description:MotivationThe three-dimensional structure of genomes makes it possible for genomic regions not adjacent in the primary sequence to be spatially proximal. These DNA contacts have been found to be related to various molecular activities. Previous methods for analyzing DNA contact maps obtained from Hi-C experiments have largely focused on studying individual interactions, forming spatial clusters composed of contiguous blocks of genomic locations, or classifying these clusters into general categories based on some global properties of the contact maps.ResultsHere, we describe a novel computational method that can flexibly identify small clusters of spatially proximal genomic regions based on their local contact patterns. Using simulated data that highly resemble Hi-C data obtained from real genome structures, we demonstrate that our method identifies spatial clusters that are more compact than methods previously used for clustering genomic regions based on DNA contact maps. The clusters identified by our method enable us to confirm functionally related genomic regions previously reported to be spatially proximal in different species. We further show that each genomic region can be assigned a numeric affinity value that indicates its degree of participation in each local cluster, and these affinity values correlate quantitatively with DNase I hypersensitivity, gene expression, super enhancer activities and replication timing in a cell type specific manner. We also show that these cluster affinity values can precisely define boundaries of reported topologically associating domains, and further define local sub-domains within each domain.Availability and implementationThe source code of BNMF and tutorials on how to use the software to extract local clusters from contact maps are available at http://yiplab.cse.cuhk.edu.hk/bnmf/Contactkevinyip@cse.cuhk.edu.hkSupplementary informationSupplementary data are available at Bioinformatics online.

| S-EPMC4908340 | biostudies-literature

CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells.

Project description:The human genome produces thousands of long noncoding RNAs (lncRNAs)-transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs.

| S-EPMC5394926 | biostudies-literature

Functional analysis of the noncoding regions of the Uukuniemi virus (Bunyaviridae) RNA segments.

Project description:The role of the variable portion of the noncoding regions (NCRs) of the three Bunyaviridae RNA segments (L, M, S) in transcription, replication, and packaging was studied using the recently developed plasmid-driven RNA polymerase I minigenome system for Uukuniemi (UUK) virus, genus Phlebovirus (11), as a model. Comparison of the different segments showed that all NCRs were sufficient to mediate transcription/replication of a minigenome but demonstrated decreased promoter strength in the order M > L > S. Chimeric minigenomes with flanking NCRs from different genome segments revealed that the number of total base pairs within the inverted, partially complementary ends was important for transcription and replication. Point mutations increasing the base-pairing potential produced increased reporter expression, indicating that complementarity between the 5' and 3' ends is crucial for promoter activity. The role of the intergenic region (IGR) located between the two open reading frames of the ambisense UUK virus S segment was analyzed by inserting this sequence element downstream of the reporter genes. The presence of the IGR was found to enhance reporter expression, demonstrating that efficient transcription termination, regulated by the IGR, is important for optimal minigenome mRNA translation. Finally, genome packaging efficacy varied for different NCRs and was strongest for L followed by M and S. Strong reporter gene activity was still observed after seven consecutive cell culture passages, indicating a selective rather than random genome-packaging mechanism. In summary, our results demonstrate that the NCRs from all three segments contain the necessary signals to initiate transcription and replication as well as packaging. Based on promoter strength, M-segment NCRs may be the preferred choice for the development of reverse genetics and minigenome rescue systems for bunyaviruses.

| S-EPMC523286 | biostudies-other

Functional annotation of HOT regions in the human genome: implications for human disease and cancer.

Project description:Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.

| S-EPMC4481521 | biostudies-literature

A high-throughput DNA FISH protocol to visualize genome regions in human cells.

Project description:Here, we describe an end-to-end high-throughput imaging protocol to visualize genomic loci in cells at high throughput using DNA fluorescence in situ hybridization, automated microscopy, and computational analysis. This is particularly useful for quantifying patterns of heterogeneity in relative gene positioning or differences within subpopulations of cells. We focus on important experimental design and execution steps in this one-week protocol, suggest ways to ensure and verify data quality, and provide practical solutions to common problems. For complete details on the generation and use of this protocol, please refer to Finn et al. (2019).

| S-EPMC8377592 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data