Featured
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Article
| Open AccessNon-parametric genetic prediction of complex traits with latent Dirichlet process regression models
Genetic prediction of complex traits with polygenic architecture has wide application from animal breeding to disease prevention. Here, Zeng and Zhou develop a non-parametric genetic prediction method based on latent Dirichlet Process regression models.
- Ping Zeng
- & Xiang Zhou
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Article
| Open AccessAn in-silico approach to predict and exploit synthetic lethality in cancer metabolism
Exploiting synthetic lethality is a promising approach for cancer therapy. Here, the authors present an approach to identifying such interactions by finding genetic minimal cut sets (gMCSs) that block cancer proliferation, and apply it to study the lethality of RRM1 inhibition in multiple myeloma.
- Iñigo Apaolaza
- , Edurne San José-Eneriz
- & Francisco J. Planes
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Article
| Open AccessIntegrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants
Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.
- Michelle L. Krishnan
- , Juliette Van Steenwinckel
- & Pierre Gressens
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Article
| Open AccessTopologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation
Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.
- Nathan Harmston
- , Elizabeth Ing-Simmons
- & Boris Lenhard
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Article
| Open AccessStromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer
Stromal cells contribute to tumor development but the mechanisms regulating this process are still unclear. Here the authors analyze gene expression profiles in the prostate and show that stromal gene signature changes ahead of the epithelial gene signature as prostate cancer initiates and progresses.
- Svitlana Tyekucheva
- , Michaela Bowden
- & Massimo Loda
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Article
| Open AccessUsing ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes
Variants causing loss of function (LoF) of human genes have clinical implications. Here, the authors present a method to predict disease-causing potential of LoF variants, ALoFT (annotation of Loss-of-Function Transcripts) and show its application to interpreting LoF variants in different contexts.
- Suganthi Balasubramanian
- , Yao Fu
- & Mark Gerstein
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Article
| Open AccessOn the performance of pre-microRNA detection algorithms
As the experimental discovery of microRNAs (miRNAs) is cumbersome, computational tools have been developed for the prediction of pre-miRNAs. Here the authors develop a framework to assess the performance of existing and novel pre-miRNA prediction tools and provide guidelines for selecting an appropriate approach for a given data set.
- Müşerref Duygu Saçar Demirci
- , Jan Baumbach
- & Jens Allmer
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Article
| Open AccessAn integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network
Protein stability modulation by E3 ubiquitin ligases is an important layer of functional regulation, but screening for E3 ligase-substrate interactions is time-consuming and costly. Here, the authors take an in silico naïve Bayesian classifier approach to integrate multiple lines of evidence for E3-substrate prediction, enabling prediction of the proteome-wide human E3 ligase interaction network.
- Yang Li
- , Ping Xie
- & Fuchu He
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Article
| Open AccessEstimating the human mutation rate from autozygous segments reveals population differences in human mutational processes
Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.
- Vagheesh M. Narasimhan
- , Raheleh Rahbari
- & Richard Durbin
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Article
| Open AccessThe origin of a primordial genome through spontaneous symmetry breaking
Early molecules of life likely served both as templates and catalysts, raising the question of how functionally distinct genomes and enzymes arose. Here, the authors show that conflict between evolution at the molecular and cellular levels can drive functional differentiation of the two strands of self-replicating molecules and lead to copy number differences between the two.
- Nobuto Takeuchi
- , Paulien Hogeweg
- & Kunihiko Kaneko
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Article
| Open AccessAnnotating pathogenic non-coding variants in genic regions
While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.
- Sahar Gelfman
- , Quanli Wang
- & David B. Goldstein
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Article
| Open AccessUnraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures
Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.
- Faiz M. Khan
- , Stephan Marquardt
- & Brigitte M. Pützer
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Article
| Open AccessBayesian association scan reveals loci associated with human lifespan and linked biomarkers
Along with various environmental factors, a complex genetic architecture influences human lifespan. Here, McDaid and colleagues reveal novel loci associated with human lifespan and linked biomarkers by Bayesian association scan.
- Aaron F. McDaid
- , Peter K. Joshi
- & Zoltán Kutalik
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Article
| Open AccessPhysical limits to biomechanical sensing in disordered fibre networks
Cells in the connective tissue are surrounded by a heterogeneous network of biopolymers. Here, the authors investigate how such heterogeneity affects cellular mechanosensing by simulating the deformation response of experimental and modelled biopolymer networks to locally applied forces.
- Farzan Beroz
- , Louise M. Jawerth
- & Ned S. Wingreen
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Article
| Open AccessDe novo active sites for resurrected Precambrian enzymes
The emergence of novel catalytic functions in ancient proteins likely played a role in the evolution of modern enzymes. Here, the authors use protein sequences from Precambrian beta-lactamases and demonstrate that a single hydrophobic-to-ionizable amino acid mutation can lead to substantial Kemp eliminase activity.
- Valeria A. Risso
- , Sergio Martinez-Rodriguez
- & Jose M. Sanchez-Ruiz
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Article
| Open AccessReversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets
Increased availability of large-scale molecular profiling has enabled system-level monitoring of molecular effects of candidate therapeutics. Here, the authors take advantage of such data to show that the ability of a drug to reverse cancer-associated gene expression changes is indicative of itsin vitroanti-proliferative efficacy, allowing them to identify novel compounds against liver cancer.
- Bin Chen
- , Li Ma
- & Atul J. Butte
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Article
| Open AccessSkin parasite landscape determines host infectiousness in visceral leishmaniasis
Parasitemia has been considered the main determinant of visceral leishmaniasis transmission. By combining imaging, qPCR and experimental xenodiagnoses with mathematical models, Doehl et al. argue that the patchy landscape of parasites in the skin is necessary to explain infectiousness.
- Johannes S. P. Doehl
- , Zoe Bright
- & Paul M. Kaye
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Article
| Open AccessGaining comprehensive biological insight into the transcriptome by performing a broad-spectrum RNA-seq analysis
RNA-seq is widely used for transcriptome analysis. Here, the authors analyse a wide spectrum of RNA-seq workflows and present a comprehensive analysis protocol named RNACocktail as well as a computational pipeline leveraging the widely used tools for accurate RNA-seq analysis.
- Sayed Mohammad Ebrahim Sahraeian
- , Marghoob Mohiyuddin
- & Hugo Y. K. Lam
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Article
| Open AccessA pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay
Nonsense-mediated decay (NMD) eliminates transcripts with premature stop codons and has been linked to cancer genesis. Here, the authors develop an algorithm to predict NMD and perform a pan-cancer analysis that finds that some hypermutated cancers are dependent on mutations that elicit NMD.
- Zhiyuan Hu
- , Christopher Yau
- & Ahmed Ashour Ahmed
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Article
| Open AccessGrowth-coupled overproduction is feasible for almost all metabolites in five major production organisms
Coupling of growth and product synthesis is an important principle in metabolic engineering, but its range of applicability is unclear. Here, the authors use a dedicated computational framework to study the feasibility of coupling the production of metabolites to growth in the genome-scale metabolic models of five production organisms, and show that coupling can be achieved for most metabolites.
- Axel von Kamp
- & Steffen Klamt
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Article
| Open AccessLipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission
The spatiotemporal regulation of membrane scaffolds recruitment and coupling between membrane deformation and fission in endocytosis are unclear. Here the authors show that lipid conversion at endocytic pits recruits SNX9, which couples local membrane constriction to fission in endocytosis.
- Johannes Schöneberg
- , Martin Lehmann
- & Frank Noé
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Article
| Open AccessReconstructing cell cycle pseudo time-series via single-cell transcriptome data
In single-cell RNA sequencing data of heterogeneous cell populations, cell cycle stage of individual cells would often be informative. Here, the authors introduce a computational model to reconstruct a pseudo-time series from single cell transcriptome data, identify the cell cycle stages, identify candidate cell cycle-regulated genes and recover the methylome changes during the cell cycle.
- Zehua Liu
- , Huazhe Lou
- & Ting Chen
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Article
| Open AccessA BaSiC tool for background and shading correction of optical microscopy images
Accurate quantification of bioimaging data is often confounded by uneven illumination (shading) in space and background variation in time. Here the authors present BaSiC, a Fiji plugin solving both issues. It requires fewer input images and is more robust to artefacts than existing shading correction tools.
- Tingying Peng
- , Kurt Thorn
- & Nassir Navab
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Article
| Open AccessCross-orientation suppression in visual area V2
V2 neurons exhibit complex and diverse selectivity for visual features. Here the authors use a statistical analytical framework to model V2 responses to natural stimuli and find three organizing principles, chief among them is the cross-orientation suppression that increases response selectivity.
- Ryan J. Rowekamp
- & Tatyana O. Sharpee
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Article
| Open AccessA molecular portrait of microsatellite instability across multiple cancers
Some cancers with DNA mismatch repair deficiency display microsatellite instability. Here the authors analyse twenty three cancer types at the exome and whole-genome level, and identify loci with recurrent microsatellite instability that could be used to identify patients who would benefit from immunotherapy.
- Isidro Cortes-Ciriano
- , Sejoon Lee
- & Peter J. Park
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Correspondence
| Open AccessCorrespondence: DNA shape is insufficient to explain binding
- Matthew J. Rossi
- , William K.M. Lai
- & B. Franklin Pugh
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Article
| Open AccessSingle-cell entropy for accurate estimation of differentiation potency from a cell’s transcriptome
Robust quantification of the differentiation potential of single cells is a task of great importance. Here the authors integrate single-cell RNA-Seq profiles with a cellular interaction network to compute the signaling entropy, and show that it can identify normal and cancer stem-cell phenotypes.
- Andrew E. Teschendorff
- & Tariq Enver
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Article
| Open AccessSmooth 2D manifold extraction from 3D image stack
Maximum Intensity Projection is a common tool to represent 3D biological imaging data in a 2D space, but it creates artefacts. Here the authors develop Smooth Manifold Extraction, an ImageJ/Fiji plugin, to preserve local spatial relationships when extracting the content of a 3D volume to a 2D space.
- Asm Shihavuddin
- , Sreetama Basu
- & Auguste Genovesio
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Article
| Open AccessSystematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data
There are no robust methods for systematically identifying mutation-specific synthetic lethal (SL) partners in cancer. Here, the authors develop a computational algorithm that uses pan-cancer data to detect mutation-andcancer-specific SL partners and they validate a novel SL interaction between mutant IDH and loss of ACACA in leukaemia.
- Subarna Sinha
- , Daniel Thomas
- & David L. Dill
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Article
| Open AccessCancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification
Tumour expression profiling is currently used for prognostic and predictive purposes without taking into account the intra patient heterogeneity. Here the authors show that cancer cell specific signatures overcome the tumour heterogeneity effect and result in better classification of colorectal cancer patients.
- Philip D. Dunne
- , Matthew Alderdice
- & Mark Lawler
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Article
| Open AccessRedesigning metabolism based on orthogonality principles
Growth-coupled designs for chemical production are limited by native metabolic networks’ optimality for growth. Here, the authors introduce pathway orthogonality as a measure of the independence of biomass and chemical production pathways, identify metabolic valves that allow substrate utilization to be switched between the two, and demonstrate advantages of orthogonal designs.
- Aditya Vikram Pandit
- , Shyam Srinivasan
- & Radhakrishnan Mahadevan
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Article
| Open AccessMiCASA is a new method for quantifying cellular organization
There are few methods available that can quantify relationships between cell types in tissue images. Here the authors present a quantitative method to evaluate cellular organization, validated in the mouse thymus and spinal cord, called Multitaper Circularly Averaged Spectral Analysis (MiCASA).
- Andrew Sornborger
- , Jie Li
- & Nancy R. Manley
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Article
| Open AccessA complete tool set for molecular QTL discovery and analysis
Analysis of molecular quantitative trait loci (molQTL) can help interpret genome-wide association studies and requires efficient approaches to correct for multiple testing. This study describes a bioinformatics toolkit called QTLtool that can handle large data sets and quickly perform multiple types of molQTL analyses.
- Olivier Delaneau
- , Halit Ongen
- & Emmanouil T. Dermitzakis
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Article
| Open AccessAn integrated model for detecting significant chromatin interactions from high-resolution Hi-C data
Genome-wide chromosome conformation capture has helped us identify features of genome topology influencing biology but requires careful statistical analysis. Here the authors present HiC-DC, a bioinformatics method that can detect statistically significant regulatory interactions.
- Mark Carty
- , Lee Zamparo
- & Christina S. Leslie
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Article
| Open AccessA hybrid cloud read aligner based on MinHash and kmer voting that preserves privacy
Outsourcing computation for genomic data processing offers the ability to allocate massive computing power and storage on demand. Here, Popic and Batzoglou develop a hybrid cloud aligner for sequence read mapping that preserves privacy with competitive accuracy and speed.
- Victoria Popic
- & Serafim Batzoglou
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Article
| Open AccessWhole genome analysis of a schistosomiasis-transmitting freshwater snail
Biomphalaria glabrata is a fresh water snail that acts as a host for trematode Schistosoma mansoni that causes intestinal infection in human. This work describes the genome and transcriptome analyses from 12 different tissues of B glabrata, and identify genes for snail behavior and evolution.
- Coen M. Adema
- , LaDeana W. Hillier
- & Richard K. Wilson
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Article
| Open AccessAnalysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection
Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.
- Rileen Sinha
- , Andrew G. Winer
- & A. Ari Hakimi
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Article
| Open AccessExchange pathways of plastoquinone and plastoquinol in the photosystem II complex
Plastoquinone (PLQ) shuttles electrons between photosystem II (PSII) and cytochrome b6f. Here the authors perform molecular dynamics simulations and propose that PLQ enters the exchange cavity of PSII by a promiscuous diffusion mechanism whereby three different channels each act as entry and exit points.
- Floris J. Van Eerden
- , Manuel N. Melo
- & Siewert J. Marrink
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Article
| Open AccessTradict enables accurate prediction of eukaryotic transcriptional states from 100 marker genes
Global patterns of gene transcription can be represented with reduced dimensionality. Here, the authors devise a method called Tradict that learns and uses 100 marker genes to predict transcriptome-wide pathway expression levels and patterns that reflect cell activity and state.
- Surojit Biswas
- , Konstantin Kerner
- & Philip A. Wigge
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Article
| Open AccessSubsampling scaling
We can often observe only a small fraction of a system, which leads to biases in the inference of its global properties. Here, the authors develop a framework that enables overcoming subsampling effects, apply it to recordings from developing neural networks, and find that neural networks become critical as they mature.
- A. Levina
- & V. Priesemann
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Article
| Open AccessSimilarity in viral and host promoters couples viral reactivation with host cell migration
The coevolution of viruses and host cells can be mapped with interactomics. Here the authors identify coupling of human and viral promoters, and show that HIV-reactivation from dormancy is coincident with migration of HIV-infected cells owing to coupling of human CXCR4 and HIV LTR promoters.
- Kathrin Bohn-Wippert
- , Erin N. Tevonian
- & Roy D. Dar
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Article
| Open AccessReconstructing 3D deformation dynamics for curved epithelial sheet morphogenesis from positional data of sparsely-labeled cells
Quantifying deformation patterns of curved epithelial sheets is challenging owing to imaging difficulties. Here the authors develop a method to obtain a quantitative description of 3D tissue deformation dynamics from a small set of cell positional data and applied it to chick forebrain morphogenesis.
- Yoshihiro Morishita
- , Ken-ichi Hironaka
- & Daisuke Ohtsuka
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Article
| Open AccessNoumeavirus replication relies on a transient remote control of the host nucleus
Large dsDNA viruses either replicate in or disrupt the nucleus to gain access to host RNA polymerases, or they rely on virus-encoded, packaged RNA polymerases. Here, the authors show that Noumeavirus replicates in the cytoplasm and relies on a transient recruitment of nuclear proteins to initiate replication.
- Elisabeth Fabre
- , Sandra Jeudy
- & Chantal Abergel
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Article
| Open AccessA computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
The identification of master regulator genes that may be manipulatedin vitro to regulate reprogramming has been difficult. Here, the authors use a computational systems approach to identify three genes (FoxA1, Nkx3.1and the androgen receptor) that can reprogramme fibroblasts to prostate tissue.
- Flaminia Talos
- , Antonina Mitrofanova
- & Michael M. Shen
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Article
| Open AccessExercise contagion in a global social network
Some argue that health-related behaviours, such as obesity, are contagious, but empirical evidence of health contagion remains inconclusive. Here, using a large scale quasi-experiment in a global network of runners, Aral and Nicolaides show that this type of contagion exists in fitness behaviours.
- Sinan Aral
- & Christos Nicolaides
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Article
| Open AccessA new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
- Alexandre Beautrait
- , Justine S. Paradis
- & Michel Bouvier
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Article
| Open AccessGenome assembly with in vitro proximity ligation data and whole-genome triplication in lettuce
Genome assembly for many plant species can be challenging due to large size and high repeat content. Here, the authors usein vitroproximity ligation to assemble the genome of lettuce, revealing a family-specific triplication event and providing a comprehensive reference genome for a member of the Compositae.
- Sebastian Reyes-Chin-Wo
- , Zhiwen Wang
- & Richard W. Michelmore
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Article
| Open AccessComputational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer
Dysregulation of microRNAs is thought to be important for metastasis in castration-resistant prostate cancer (CRPC), but its drivers are unknown. Here, the authors use computational analysis to identify HOXC6 and NKX2-2 in addition to AR as alternative drivers of dysregulated miRNA expression in CRPC.
- Mengzhu Xue
- , Haiyue Liu
- & Peng Wang
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Article
| Open AccessMulti-scale chromatin state annotation using a hierarchical hidden Markov model
The impact of chromatin structure on gene expression makes it integral to our understanding of developmental and disease processes. Here, the authors introduce a hierarchical hidden Markov model to systematically annotate chromatin states at multiple length scales, and demonstrate its utility for the elucidation of the role of chromatin structure in gene expression.
- Eugenio Marco
- , Wouter Meuleman
- & Guo-Cheng Yuan
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