ChromHMM outputs both the learned chromatin-state model parameters and the chromatin-state assignments for each genomic position. The learned emission and transition parameters are returned in both ...text and image format (Fig. 1), automatically grouping chromatin states with similar emission parameters or proximal genomic locations, although a user-specified reordering can also be used (Supplementary Figs. 12 and Supplementary Note). ChromHMM enables the study of the likely biological roles of each chromatin state based on enrichment in diverse external annotations and experimental data, shown as heat maps and tables (Fig. 1), both for direct genomic overlap and at various distances from a chromatin state.
With hundreds of epigenomic maps, the opportunity arises to exploit the correlated nature of epigenetic signals, across both marks and samples, for large-scale prediction of additional datasets. ...Here, we undertake epigenome imputation by leveraging such correlations through an ensemble of regression trees. We impute 4,315 high-resolution signal maps, of which 26% are also experimentally observed. Imputed signal tracks show overall similarity to observed signals and surpass experimental datasets in consistency, recovery of gene annotations and enrichment for disease-associated variants. We use the imputed data to detect low-quality experimental datasets, to find genomic sites with unexpected epigenomic signals, to define high-priority marks for new experiments and to delineate chromatin states in 127 reference epigenomes spanning diverse tissues and cell types. Our imputed datasets provide the most comprehensive human regulatory region annotation to date, and our approach and the ChromImpute software constitute a useful complement to large-scale experimental mapping of epigenomic information.
A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although ...individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal 'chromatin states' in human T cells, based on recurrent and spatially coherent combinations of chromatin marks. We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, large-scale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.
Time series microarray experiments are widely used to study dynamical biological processes. Due to the cost of microarray experiments, and also in some cases the limited availability of biological ...material, about 80% of microarray time series experiments are short (3-8 time points). Previously short time series gene expression data has been mainly analyzed using more general gene expression analysis tools not designed for the unique challenges and opportunities inherent in short time series gene expression data.
We introduce the Short Time-series Expression Miner (STEM) the first software program specifically designed for the analysis of short time series microarray gene expression data. STEM implements unique methods to cluster, compare, and visualize such data. STEM also supports efficient and statistically rigorous biological interpretations of short time series data through its integration with the Gene Ontology.
The unique algorithms STEM implements to cluster and compare short time series gene expression data combined with its visualization capabilities and integration with the Gene Ontology should make STEM useful in the analysis of data from a significant portion of all microarray studies. STEM is available for download for free to academic and non-profit users at http://www.cs.cmu.edu/~jernst/stem.
A large-scale application of the "stacked modeling" approach for chromatin state discovery previously provides a single "universal" chromatin state annotation of the human genome based jointly on ...data from many cell and tissue types. Here, we produce an analogous chromatin state annotation for mouse based on 901 datasets assaying 14 chromatin marks in 26 cell or tissue types. To characterize each chromatin state, we relate the states to external annotations and compare them to analogously defined human states. We expect the universal chromatin state annotation for mouse to be a useful resource for studying this key model organism's genome.
Identifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we develop ...a method to learn a score of evidence of conservation at the functional genomics level by integrating information from a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The method, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains neural networks to generate this score for the human and mouse genomes. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations. Analysis with independent datasets shows the score also highlights loci associated with similar phenotypes in both species. LECIF will be a resource for mouse model studies by identifying loci whose functional genomic properties are likely conserved.
Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), ...and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.
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•Genome-wide annotation of cis-regulatory elements at four reprogramming stages•Somatic enhancer silencing is initiated through several OSK-induced mechanisms•Stepwise pluripotency enhancer selection is dependent on collaborative TF binding•Stage-specific TFs influence OSK occupancy and enhancer selection
Oct4, Sox2, and Klf4 work collaboratively with the help of other transcription factors to change the enhancer landscape during reprogramming.
Blockchain technology has attracted tremendous attention in both academia and capital market. However, overwhelming speculations on thousands of available cryptocurrencies and numerous initial coin ...offering scams have also brought notorious debates on this emerging technology. This paper traces the development of blockchain systems to reveal the importance of decentralized applications (dApps) and the future value of blockchain. We survey the state-of-the-art dApps and discuss the direction of blockchain development to fulfill the desirable characteristics of dApps. The readers will gain an overview of dApp research and get familiar with recent developments in the blockchain.
Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner. However, the 3D organization of chromosomes during human brain development ...and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.
To model spatial changes of chromatin mark peaks over time we develop and apply ChromTime, a computational method that predicts peaks to be either expanding, contracting, or holding steady between ...time points. Predicted expanding and contracting peaks can mark regulatory regions associated with transcription factor binding and gene expression changes. Spatial dynamics of peaks provide information about gene expression changes beyond localized signal density changes. ChromTime detects asymmetric expansions and contractions, which for some marks associate with the direction of transcription. ChromTime facilitates the analysis of time course chromatin data in a range of biological systems.
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