PLoS Articles
User Collection Public
UNC-authored articles published by the Public Library of Science (PLoS)
Works (2111)
1611. ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations
- Title Tesim:
- ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations
- Creator:
- Williams II, Benfeard, Convertino, Marino, Dokholyan, Nikolay V., and Das, Jhuma
- Date of publication:
- 2015
- Abstract Tesim:
- The increased risk of developing Alzheimer’s disease (AD) is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD-related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD.Author SummaryApoE is a lipid transporter protein associated with the onset of Alzheimer’s disease. Among the three human variants, ApoE4 isoform represents the strongest genetic risk factor for the onset of Alzheimer’s disease. We identify an ApoE4-specific misfolded intermediate state that may alter multiple cellular pathways involved in cellular homeostasis of lipids and AD-related proteins. The presented structural model of the ApoE4-specific intermediate state may serve to elucidate the molecular mechanisms underlying the physiopathological functions of ApoE isoforms, and it can pave the way for the development of alternative pharmacological strategies in the treatment of Alzheimer’s disease.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/v5hc-qz44
- Identifier:
- Onescience id: 6b245d466a9b17277b06f9c8af11b240e440ae88, PMCID: PMC4623519, PMID: 26506597, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1004359
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 10
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 11
- Keyword:
- Apolipoprotein E4, Proteins, Lipids, Risk Factors, Apolipoprotein E2, Genes, Alzheimer Disease, Amino Acids, Apolipoproteins E, Homeostasis, Apolipoprotein E3, Risk, Therapeutics, APOE, and Molecular Dynamics Simulation
- Language Label:
- English
- Page Start:
- e1004359
- Person:
- Williams II, Benfeard, Convertino, Marino, Dokholyan, Nikolay V., and Das, Jhuma
- Rights Statement Label:
- In Copyright
- Source:
- cc08hp70n
1612. Resolving Structural Variability in Network Models and the Brain
- Title Tesim:
- Resolving Structural Variability in Network Models and the Brain
- Creator:
- Carlson, Jean M., Bassett, Danielle S., Mucha, Peter J., and Klimm, Florian
- Date of publication:
- 2014
- Abstract Tesim:
- Large-scale white matter pathways crisscrossing the cortex create a complex pattern of connectivity that underlies human cognitive function. Generative mechanisms for this architecture have been difficult to identify in part because little is known in general about mechanistic drivers of structured networks. Here we contrast network properties derived from diffusion spectrum imaging data of the human brain with 13 synthetic network models chosen to probe the roles of physical network embedding and temporal network growth. We characterize both the empirical and synthetic networks using familiar graph metrics, but presented here in a more complete statistical form, as scatter plots and distributions, to reveal the full range of variability of each measure across scales in the network. We focus specifically on the degree distribution, degree assortativity, hierarchy, topological Rentian scaling, and topological fractal scaling—in addition to several summary statistics, including the mean clustering coefficient, the shortest path-length, and the network diameter. The models are investigated in a progressive, branching sequence, aimed at capturing different elements thought to be important in the brain, and range from simple random and regular networks, to models that incorporate specific growth rules and constraints. We find that synthetic models that constrain the network nodes to be physically embedded in anatomical brain regions tend to produce distributions that are most similar to the corresponding measurements for the brain. We also find that network models hardcoded to display one network property (e.g., assortativity) do not in general simultaneously display a second (e.g., hierarchy). This relative independence of network properties suggests that multiple neurobiological mechanisms might be at play in the development of human brain network architecture. Together, the network models that we develop and employ provide a potentially useful starting point for the statistical inference of brain network structure from neuroimaging data.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/8bmd-et22
- Identifier:
- PMID: 24675546, PMCID: PMC3967917, Onescience id: 1ee2697bd73f1f4e1a5efe9d5ca5013005de2079, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1003491
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 3
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 10
- Keyword:
- Nerve Net, Cluster Analysis, Fractals, Brain Mapping, Models, Statistical, Brain, Cerebral Cortex, Probability, Humans, Algorithms, Models, Neurological, Software, Healthy Volunteers, Computational Biology, and Neural Pathways
- Language Label:
- English
- Page Start:
- e1003491
- Person:
- Carlson, Jean M., Bassett, Danielle S., Mucha, Peter J., and Klimm, Florian
- Rights Statement Label:
- In Copyright
- Source:
- x059cg53h
1613. Task-Based Core-Periphery Organization of Human Brain Dynamics
- Title Tesim:
- Task-Based Core-Periphery Organization of Human Brain Dynamics
- Creator:
- Wymbs, Nicholas F., Mucha, Peter J., Bassett, Danielle S., Rombach, M. Puck, Grafton, Scott T., and Porter, Mason A.
- Date of publication:
- 2013
- Abstract Tesim:
- As a person learns a new skill, distinct synapses, brain regions, and circuits are engaged and change over time. In this paper, we develop methods to examine patterns of correlated activity across a large set of brain regions. Our goal is to identify properties that enable robust learning of a motor skill. We measure brain activity during motor sequencing and characterize network properties based on coherent activity between brain regions. Using recently developed algorithms to detect time-evolving communities, we find that the complex reconfiguration patterns of the brain's putative functional modules that control learning can be described parsimoniously by the combined presence of a relatively stiff temporal core that is composed primarily of sensorimotor and visual regions whose connectivity changes little in time and a flexible temporal periphery that is composed primarily of multimodal association regions whose connectivity changes frequently. The separation between temporal core and periphery changes over the course of training and, importantly, is a good predictor of individual differences in learning success. The core of dynamically stiff regions exhibits dense connectivity, which is consistent with notions of core-periphery organization established previously in social networks. Our results demonstrate that core-periphery organization provides an insightful way to understand how putative functional modules are linked. This, in turn, enables the prediction of fundamental human capacities, including the production of complex goal-directed behavior.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/f5z2-dw19
- Identifier:
- Onescience id: 20f267616b089c3a95e76e6535c09f0602c712c7, PMCID: PMC3784512, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1003171, and PMID: 24086116
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 9
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 9
- Keyword:
- Functional magnetic resonance imaging, Optimization, Learning, Neural networks, Human learning, Cognitive science, Cognition, and Neuroimaging
- Language Label:
- English
- Page Start:
- e1003171
- Person:
- Wymbs, Nicholas F., Mucha, Peter J., Bassett, Danielle S., Rombach, M. Puck, Grafton, Scott T., and Porter, Mason A.
- Rights Statement Label:
- In Copyright
- Source:
- 8k71nr20m
1614. Evolutionary Evidence for Alternative Structure in RNA Sequence Co-variation
- Title Tesim:
- Evolutionary Evidence for Alternative Structure in RNA Sequence Co-variation
- Creator:
- Martin, Joshua S., Ritz, Justin, and Laederach, Alain
- Date of publication:
- 2013
- Abstract Tesim:
- Sequence conservation and co-variation of base pairs are hallmarks of structured RNAs. For certain RNAs (e.g. riboswitches), a single sequence must adopt at least two alternative secondary structures to effectively regulate the message. If alternative secondary structures are important to the function of an RNA, we expect to observe evolutionary co-variation supporting multiple conformations. We set out to characterize the evolutionary co-variation supporting alternative conformations in riboswitches to determine the extent to which alternative secondary structures are conserved. We found strong co-variation support for the terminator, P1, and anti-terminator stems in the purine riboswitch by extending alignments to include terminator sequences. When we performed Boltzmann suboptimal sampling on purine riboswitch sequences with terminators we found that these sequences appear to have evolved to favor specific alternative conformations. We extended our analysis of co-variation to classic alignments of group I/II introns, tRNA, and other classes of riboswitches. In a majority of these RNAs, we found evolutionary evidence for alternative conformations that are compatible with the Boltzmann suboptimal ensemble. Our analyses suggest that alternative conformations are selected for and thus likely play functional roles in even the most structured of RNAs.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/8y03-a682
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pcbi.1003152, PMID: 23935473, PMCID: PMC3723493, and Onescience id: 6731cf355c862910d051dded1e22116c0f2312c1
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 7
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 9
- Keyword:
- Introns, RNA alignment, RNA folding, Sequence analysis, Sequence alignment, Crystal structure, RNA structure, and Purines
- Language Label:
- English
- Page Start:
- e1003152
- Person:
- Martin, Joshua S., Ritz, Justin, and Laederach, Alain
- Rights Statement Label:
- In Copyright
- Source:
- z029pc870
1615. Emergence of Metastable State Dynamics in Interconnected Cortical Networks with Propagation Delays
- Title Tesim:
- Emergence of Metastable State Dynamics in Interconnected Cortical Networks with Propagation Delays
- Creator:
- Kutchko, Katrina M. and Fröhlich, Flavio
- Date of publication:
- 2013
- Abstract Tesim:
- The importance of the large number of thin-diameter and unmyelinated axons that connect different cortical areas is unknown. The pronounced propagation delays in these axons may prevent synchronization of cortical networks and therefore hinder efficient information integration and processing. Yet, such global information integration across cortical areas is vital for higher cognitive function. We hypothesized that delays in communication between cortical areas can disrupt synchronization and therefore enhance the set of activity trajectories and computations interconnected networks can perform. To evaluate this hypothesis, we studied the effect of long-range cortical projections with propagation delays in interconnected large-scale cortical networks that exhibited spontaneous rhythmic activity. Long-range connections with delays caused the emergence of metastable, spatio-temporally distinct activity states between which the networks spontaneously transitioned. Interestingly, the observed activity patterns correspond to macroscopic network dynamics such as globally synchronized activity, propagating wave fronts, and spiral waves that have been previously observed in neurophysiological recordings from humans and animal models. Transient perturbations with simulated transcranial alternating current stimulation (tACS) confirmed the multistability of the interconnected networks by switching the networks between these metastable states. Our model thus proposes that slower long-range connections enrich the landscape of activity states and represent a parsimonious mechanism for the emergence of multistability in cortical networks. These results further provide a mechanistic link between the known deficits in connectivity and cortical state dynamics in neuropsychiatric illnesses such as schizophrenia and autism, as well as suggest non-invasive brain stimulation as an effective treatment for these illnesses.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/wcz7-sv49
- Identifier:
- PMID: 24204238, Onescience id: 4c9c0b24746748388dd5a5562f29f544860e8c85, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1003304, and PMCID: PMC3812055
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 10
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 9
- Keyword:
- Computer Simulation, Brain, Humans, Nerve Net, Schizophrenia, Autistic Disorder, Models, Neurological, Cortical Synchronization, and Deep Brain Stimulation
- Language Label:
- English
- Page Start:
- e1003304
- Person:
- Kutchko, Katrina M. and Fröhlich, Flavio
- Rights Statement Label:
- In Copyright
- Source:
- 1n79hc06t
1616. Suppressed Expression of T-Box Transcription Factors Is Involved in Senescence in Chronic Obstructive Pulmonary Disease
- Title Tesim:
- Suppressed Expression of T-Box Transcription Factors Is Involved in Senescence in Chronic Obstructive Pulmonary Disease
- Creator:
- Vulimiri, Madhulika, Acquaah-Mensah, George K., McDermott, Jason E., Biswal, Shyam, and Malhotra, Deepti
- Date of publication:
- 2012
- Abstract Tesim:
- Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed; while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/9fcy-sd21
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pcbi.1002597, Onescience id: 4387f6822c04a280f77f197816cccea10812f650, PMCID: PMC3400575, and PMID: 22829758
- ISSN:
- 1553-734X and 1553-7358
- Journal Issue:
- 7
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 8
- Keyword:
- lungs, apoptosis, interactions, pathogenesis, regulatory networks, etiology, basic biological sciences, network inference, patients, algorithms, neoplasms, applied life sciences, genes, inflammation, phosphotransferases, histones, chromatin, transcription factors systems biology, signature discovery, diseases, and proteins
- Language Label:
- English
- Page Start:
- e1002597
- Person:
- Vulimiri, Madhulika, Acquaah-Mensah, George K., McDermott, Jason E., Biswal, Shyam, and Malhotra, Deepti
- Rights Statement Label:
- In Copyright
- Source:
- b2774357m
1617. Multiple Spike Time Patterns Occur at Bifurcation Points of Membrane Potential Dynamics
- Title Tesim:
- Multiple Spike Time Patterns Occur at Bifurcation Points of Membrane Potential Dynamics
- Creator:
- Sejnowski, Terrence J., Thomas, Peter J., Tiesinga, Paul H., Toups, J. Vincent, and Fellous, Jean-Marc
- Date of publication:
- 2012
- Abstract Tesim:
- The response of a neuron to repeated somatic fluctuating current injections in vitro can elicit a reliable and precisely timed sequence of action potentials. The set of responses obtained across trials can also be interpreted as the response of an ensemble of similar neurons receiving the same input, with the precise spike times representing synchronous volleys that would be effective in driving postsynaptic neurons. To study the reproducibility of the output spike times for different conditions that might occur in vivo, we somatically injected aperiodic current waveforms into cortical neurons in vitro and systematically varied the amplitude and DC offset of the fluctuations. As the amplitude of the fluctuations was increased, reliability increased and the spike times remained stable over a wide range of values. However, at specific values called bifurcation points, large shifts in the spike times were obtained in response to small changes in the stimulus, resulting in multiple spike patterns that were revealed using an unsupervised classification method. Increasing the DC offset, which mimicked an overall increase in network background activity, also revealed bifurcation points and increased the reliability. Furthermore, the spike times shifted earlier with increasing offset. Although the reliability was reduced at bifurcation points, a theoretical analysis showed that the information about the stimulus time course was increased because each of the spike time patterns contained different information about the input.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/bd2h-c497
- Identifier:
- Onescience id: 98e1a2ab04895851c59db17af0cb60043f8c6ff5, PMCID: PMC3475656, PMID: 23093916, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1002615
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 10
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 8
- Keyword:
- Computer Simulation, Action Potentials, Rats, Sprague-Dawley, Pyramidal Cells, Animals, Electric Stimulation, Neurons, Rats, Reproducibility of Results, and Models, Neurological
- Language Label:
- English
- Page Start:
- e1002615
- Person:
- Sejnowski, Terrence J., Thomas, Peter J., Tiesinga, Paul H., Toups, J. Vincent, and Fellous, Jean-Marc
- Rights Statement Label:
- In Copyright
- Source:
- 6m311x00n
1618. Chapter 10: Mining Genome-Wide Genetic Markers
- Title Tesim:
- Chapter 10: Mining Genome-Wide Genetic Markers
- Creator:
- Zhang, Zhaojun, Huang, Shunping, Zhang, Xiang, and Wang, Wei
- Date of publication:
- 2012
- Abstract Tesim:
- Genome-wide association study (GWAS) aims to discover genetic factors underlying phenotypic traits. The large number of genetic factors poses both computational and statistical challenges. Various computational approaches have been developed for large scale GWAS. In this chapter, we will discuss several widely used computational approaches in GWAS. The following topics will be covered: (1) An introduction to the background of GWAS. (2) The existing computational approaches that are widely used in GWAS. This will cover single-locus, epistasis detection, and machine learning methods that have been recently developed in biology, statistic, and computer science communities. This part will be the main focus of this chapter. (3) The limitations of current approaches and future directions.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/53pz-a518
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pcbi.1002828, PMCID: PMC3531292, PMID: 23300418, and Onescience id: d89e72a251bacf28c8d5863fa5ffdffe098b84f1
- ISSN:
- 1553-7358 and 1553-734X
- Journal Issue:
- 12
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 8
- Keyword:
- Genome-wide association studies, Phenotypes, Contingency tables, Analysis of variance, Permutation, Test statistics, Epistasis, and Chi square tests
- Language Label:
- English
- Page Start:
- e1002828
- Person:
- Zhang, Zhaojun, Huang, Shunping, Zhang, Xiang, and Wang, Wei
- Rights Statement Label:
- In Copyright
- Source:
- v118rn38s
1619. Thermodynamic Stability of Histone H3 Is a Necessary but not Sufficient Driving Force for its Evolutionary Conservation
- Title Tesim:
- Thermodynamic Stability of Histone H3 Is a Necessary but not Sufficient Driving Force for its Evolutionary Conservation
- Creator:
- Vogel, Lisa, Strahl, Brian D., Ramachandran, Srinivas, and Dokholyan, Nikolay V.
- Date of publication:
- 2011
- Abstract Tesim:
- Determining the forces that conserve amino acid positions in proteins across species is a fundamental pursuit of molecular evolution. Evolutionary conservation is driven by either a protein's function or its thermodynamic stability. Highly conserved histone proteins offer a platform to evaluate these driving forces. While the conservation of histone H3 and H4 “tail” domains and surface residues are driven by functional importance, the driving force behind the conservation of buried histone residues has not been examined. Using a computational approach, we determined the thermodynamically preferred amino acids at each buried position in H3 and H4. In agreement with what is normally observed in proteins, we find a significant correlation between thermodynamic stability and evolutionary conservation in the buried residues in H4. In striking contrast, we find that thermodynamic stability of buried H3 residues does not correlate with evolutionary conservation. Given that these H3 residues are not post-translationally modified and only regulate H3-H3 and H3-H4 stabilizing interactions, our data imply an unknown function responsible for driving conservation of these buried H3 residues.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/trh0-9q98
- Identifier:
- Onescience id: bc3501f9503be359c5eab0a7c0d509b73160de7e, Publisher DOI: https://doi.org/10.1016/j.bpj.2010.12.562, and PMCID: PMC3017104
- ISSN:
- 1553-734X and 1553-7358
- Journal Issue:
- 3 S1
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 100
- Keyword:
- Nucleosomes, Thermodynamics, Histones, Entropy, Fungal evolution, Multiple alignment calculation, Protein sequencing, and Sequence databases
- Language Label:
- English
- Page End:
- 67a
- Page Start:
- 66a
- Person:
- Vogel, Lisa, Strahl, Brian D., Ramachandran, Srinivas, and Dokholyan, Nikolay V.
- Rights Statement Label:
- In Copyright
- Source:
- vq27zw647
1620. Discovering Transcription Factor Binding Sites in Highly Repetitive Regions of Genomes with Multi-Read Analysis of ChIP-Seq Data
- Title Tesim:
- Discovering Transcription Factor Binding Sites in Highly Repetitive Regions of Genomes with Multi-Read Analysis of ChIP-Seq Data
- Creator:
- Keleş, Sündüz, Chung, Dongjun, Bresnick, Emery H., Dewey, Colin, Li, Bo, Liang, Kun, Kuan, Pei Fen, and Sanalkumar, Rajendran
- Date of publication:
- 2011
- Abstract Tesim:
- Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is rapidly replacing chromatin immunoprecipitation combined with genome-wide tiling array analysis (ChIP-chip) as the preferred approach for mapping transcription-factor binding sites and chromatin modifications. The state of the art for analyzing ChIP-seq data relies on using only reads that map uniquely to a relevant reference genome (uni-reads). This can lead to the omission of up to 30% of alignable reads. We describe a general approach for utilizing reads that map to multiple locations on the reference genome (multi-reads). Our approach is based on allocating multi-reads as fractional counts using a weighted alignment scheme. Using human STAT1 and mouse GATA1 ChIP-seq datasets, we illustrate that incorporation of multi-reads significantly increases sequencing depths, leads to detection of novel peaks that are not otherwise identifiable with uni-reads, and improves detection of peaks in mappable regions. We investigate various genome-wide characteristics of peaks detected only by utilization of multi-reads via computational experiments. Overall, peaks from multi-read analysis have similar characteristics to peaks that are identified by uni-reads except that the majority of them reside in segmental duplications. We further validate a number of GATA1 multi-read only peaks by independent quantitative real-time ChIP analysis and identify novel target genes of GATA1. These computational and experimental results establish that multi-reads can be of critical importance for studying transcription factor binding in highly repetitive regions of genomes with ChIP-seq experiments.
- Resource type:
- Article
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/pfcm-n590
- Identifier:
- PMID: 21779159, Onescience id: b2273ac7ba2f3c4191d7d236d2a8371e8e16939f, PMCID: PMC3136429, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1002111
- ISSN:
- 1553-734X and 1553-7358
- Journal Issue:
- 7
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 7
- Keyword:
- Reproducibility of Results, Genomics, Chromatin Immunoprecipitation, STAT1 Transcription Factor, HeLa Cells, Binding Sites, GATA1 Transcription Factor, Sequence Analysis, DNA, Animals, Genome, Base Composition, Repetitive Sequences, Nucleic Acid, Mice, Humans, High-Throughput Screening Assays, and Chromosome Mapping
- Language Label:
- English
- Page Start:
- e1002111
- Person:
- Keleş, Sündüz, Chung, Dongjun, Bresnick, Emery H., Dewey, Colin, Li, Bo, Liang, Kun, Kuan, Pei Fen, and Sanalkumar, Rajendran
- Rights Statement Label:
- In Copyright
- Source:
- rj430c33h
Collection Details
- Total items
-
2111
- Size
-
unknown
- Date created
-
February 2, 2022