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Trac-looping measures genome structure and chromatin accessibility.

ABSTRACT: Long-range chromatin interactions play critical roles in genome organization and regulation of transcription. We now report transposase-mediated analysis of chromatin looping (Trac-looping) for simultaneous detection of multiscale genome-wide chromatin interactions among regulatory elements and chromatin accessibility. With this technique, a bivalent oligonucleotide linker is inserted between two interacting regions such that the chromatin interactions are captured without prior chromatin fragmentation and proximity-based ligation. Application of Trac-looping to human CD4+ T cells revealed substantial reorganization of enhancer-promoter interactions associated with changes in gene expression after T cell receptor stimulation.

SUBMITTER: Lai B

PROVIDER: S-EPMC7212307 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Trac-looping measures genome structure and chromatin accessibility.

Lai Binbin B Tang Qingsong Q Jin Wenfei W Hu Gangqing G Wangsa Darawalee D Cui Kairong K Stanton Benjamin Z BZ Ren Gang G Ding Yi Y Zhao Ming M Liu Shuai S Song Jiuzhou J Ried Thomas T Zhao Keji K

Nature methods 20180827 9

Long-range chromatin interactions play critical roles in genome organization and regulation of transcription. We now report transposase-mediated analysis of chromatin looping (Trac-looping) for simultaneous detection of multiscale genome-wide chromatin interactions among regulatory elements and chromatin accessibility. With this technique, a bivalent oligonucleotide linker is inserted between two interacting regions such that the chromatin interactions are captured without prior chromatin fragme ...[more]

PMID: 30150754

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Trac-looping measures genome structure and chromatin accessibility

Project description:Interaction between different chromatin regions plays critical roles in genome organization and regulation of transcription. Existing technologies of analyzing genome-wide chromatin interactions rely on in vitro proximity-based ligation of interacting chromatin fragments and thus are prone to potential artifacts. We now report a novel technique, Transposase-mediated Analysis of Chromatin loops (TrAC-loop), for detection of genome-wide chromatin interactions between regulatory regions. With this technique, a bivalent oligonucleotide linker is inserted between two interacting chromatin regions such that the distant interacting chromatin regions can be directly amplified by PCR and thus avoids the prior chromatin fragmentation and subsequent error-prone re-ligation steps. TrAC-loop selectively targets accessible regions, which effectively reduces the sequencing cost for detecting promoter-enhancer interactions at high resolution. Application of TrAC-loop to human CD4+ T cells reveals a substantial reorganization of enhancer-promoter interaction associated with changes in gene expression upon TCR stimulation.

2018-07-12 | GSE87254 | GEO

Temporal inhibition of chromatin looping and enhancer accessibility during neuronal remodeling.

Project description:During development, looping of an enhancer to a promoter is frequently observed in conjunction with temporal and tissue-specific transcriptional activation. The chromatin insulator-associated protein Alan Shepard (Shep) promotes Drosophila post-mitotic neuronal remodeling by repressing transcription of master developmental regulators, such as brain tumor (brat), specifically in maturing neurons. Since insulator proteins can promote looping, we hypothesized that Shep antagonizes brat promoter interaction with an as yet unidentified enhancer. Using chromatin conformation capture and reporter assays, we identified two enhancer regions that increase in looping frequency with the brat promoter specifically in pupal brains after Shep depletion. The brat promoters and enhancers function independently of Shep, ruling out direct repression of these elements. Moreover, ATAC-seq in isolated neurons demonstrates that Shep restricts chromatin accessibility of a key brat enhancer as well as other enhancers genome-wide in remodeling pupal but not larval neurons. These enhancers are enriched for chromatin targets of Shep and are located at Shep-inhibited genes, suggesting direct Shep inhibition of enhancer accessibility and gene expression during neuronal remodeling. Our results provide evidence for temporal regulation of chromatin looping and enhancer accessibility during neuronal maturation.

| S-EPMC8568962 | biostudies-literature

Genome-Wide Association between Transcription Factor Expression and Chromatin Accessibility Reveals Regulators of Chromatin Accessibility.

Project description:To better understand genome regulation, it is important to uncover the role of transcription factors in the process of chromatin structure establishment and maintenance. Here we present a data-driven approach to systematically characterise transcription factors that are relevant for this process. Our method uses a linear mixed modelling approach to combine datasets of transcription factor binding motif enrichments in open chromatin and gene expression across the same set of cell lines. Applying this approach to the ENCODE dataset, we confirm already known and imply numerous novel transcription factors that play a role in the establishment or maintenance of open chromatin. In particular, our approach rediscovers many factors that have been annotated as pioneer factors.

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Three-dimensional Epigenome Statistical Model: Genome-wide Chromatin Looping Prediction.

Project description:This study aims to understand through statistical learning the basic biophysical mechanisms behind three-dimensional folding of epigenomes. The 3DEpiLoop algorithm predicts three-dimensional chromatin looping interactions within topologically associating domains (TADs) from one-dimensional epigenomics and transcription factor profiles using the statistical learning. The predictions obtained by 3DEpiLoop are highly consistent with the reported experimental interactions. The complex signatures of epigenomic and transcription factors within the physically interacting chromatin regions (anchors) are similar across all genomic scales: genomic domains, chromosomal territories, cell types, and different individuals. We report the most important epigenetic and transcription factor features used for interaction identification either shared, or unique for each of sixteen (16) cell lines. The analysis shows that CTCF interaction anchors are enriched by transcription factors yet deficient in histone modifications, while the opposite is true in the case of RNAP II mediated interactions. The code is available at the repository https://bitbucket.org/4dnucleome/3depiloop .

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Genome-wide chromatin accessibility is restricted by ANP32E.

Project description:Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.

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Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping.

Project description:BackgroundTo investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we create a catalog of genetic variants associated with three stages of transcriptional cis-regulation in primary human coronary artery vascular smooth muscle cells (HCASMCs).ResultsWe use a pooling approach with HCASMC lines to map regulatory variants that mediate binding of the CAD-associated transcription factor TCF21 with ChIPseq studies (bQTLs), variants that regulate chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with Hi-C methods (clQTLs). We examine the overlap of these QTLs and their relationship to smooth muscle-specific genes and transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlate to lead SNPs where they show allelic effects. By utilizing genome editing, we verify that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease-associated TGFB1-SMAD3 pathway to the CAD-associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping.ConclusionsTogether, these studies represent the most thorough mapping of multiple QTL types in a highly disease-relevant primary cultured cell type and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk.

| S-EPMC7278146 | biostudies-literature

Higher order chromatin structure at the X-inactivation center via looping DNA.

Project description:In mammals, the silencing step of the X-chromosome inactivation (XCI) process is initiated by the non-coding Xist RNA. Xist is known to be controlled by the non-coding Xite and Tsix loci, but the mechanisms by which Tsix and Xite regulate Xist are yet to be fully elucidated. Here, we examine the role of higher order chromatin structure across the 100-kb region of the mouse X-inactivation center (Xic) and map domains of specialized chromatin in vivo. By hypersensitive site mapping and chromosome conformation capture (3C), we identify two domains of higher order chromatin structure. Xite makes looping interactions with Tsix, while Xist makes contacts with Jpx/Enox, another non-coding gene not previously implicated in XCI. These regions interact in a developmentally-specific and sex-specific manner that is consistent with a regulatory role in XCI. We propose that dynamic changes in three-dimensional architecture leads to formation of separate chromatin hubs in Tsix and Xist that together regulate the initiation of X-chromosome inactivation.

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Acute depletion of CTCF rewires genome-wide chromatin accessibility.

Project description:BackgroundThe transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription.ResultsHere, we systematically integrate multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, and CRISPR-Cas9 survival dropout screens, and time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewires genome-wide chromatin accessibility. Increased accessible chromatin regions are frequently located adjacent to CTCF-binding sites at promoter regions and insulator sites associated with enhanced transcription of nearby genes. In addition, we use CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners. We successfully identify 40 candidates, including multiple established partners. Interestingly, many CTCF co-regulators that have alterations of their respective downstream gene expression do not show changes of their own expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription.ConclusionsThis study highlights that CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation.

| S-EPMC8386078 | biostudies-literature

A synergistic DNA logic predicts genome-wide chromatin accessibility.

Project description:Enhancers and promoters commonly occur in accessible chromatin characterized by depleted nucleosome contact; however, it is unclear how chromatin accessibility is governed. We show that log-additive cis-acting DNA sequence features can predict chromatin accessibility at high spatial resolution. We develop a new type of high-dimensional machine learning model, the Synergistic Chromatin Model (SCM), which when trained with DNase-seq data for a cell type is capable of predicting expected read counts of genome-wide chromatin accessibility at every base from DNA sequence alone, with the highest accuracy at hypersensitive sites shared across cell types. We confirm that a SCM accurately predicts chromatin accessibility for thousands of synthetic DNA sequences using a novel CRISPR-based method of highly efficient site-specific DNA library integration. SCMs are directly interpretable and reveal that a logic based on local, nonspecific synergistic effects, largely among pioneer TFs, is sufficient to predict a large fraction of cellular chromatin accessibility in a wide variety of cell types.

| S-EPMC5052050 | biostudies-literature

ATACgraph: Profiling Genome-Wide Chromatin Accessibility From ATAC-seq.

Project description:Assay for transposase-accessible chromatin using sequencing data (ATAC-seq) is an efficient and precise method for revealing chromatin accessibility across the genome. Most of the current ATAC-seq tools follow chromatin immunoprecipitation sequencing (ChIP-seq) strategies that do not consider ATAC-seq-specific properties. To incorporate specific ATAC-seq quality control and the underlying biology of chromatin accessibility, we developed a bioinformatics software named ATACgraph for analyzing and visualizing ATAC-seq data. ATACgraph profiles accessible chromatin regions and provides ATAC-seq-specific information including definitions of nucleosome-free regions (NFRs) and nucleosome-occupied regions. ATACgraph also allows identification of differentially accessible regions between two ATAC-seq datasets. ATACgraph incorporates the docker image with the Galaxy platform to provide an intuitive user experience via the graphical interface. Without tedious installation processes on a local machine or cloud, users can analyze data through activated websites using pre-designed workflows or customized pipelines composed of ATACgraph modules. Overall, ATACgraph is an effective tool designed for ATAC-seq for biologists with minimal bioinformatics knowledge to analyze chromatin accessibility. ATACgraph can be run on any ATAC-seq data with no limit to specific genomes. As validation, we demonstrated ATACgraph on human genome to showcase its functions for ATAC-seq interpretation. This software is publicly accessible and can be downloaded at https://github.com/RitataLU/ATACgraph.

| S-EPMC7874078 | biostudies-literature

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