scholarly journals Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

2019 ◽  
Author(s):  
Gustavo A. Ruiz Buendía ◽  
Marion Leleu ◽  
Flavia Marzetta ◽  
Ludovica Vanzan ◽  
Jennifer Y. Tan ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Three Dimensional ◽  
Repeat Expansion ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Ctg Repeats ◽  
Repeat Tract ◽  
Chromatin Interactions ◽  
Chromatin Folding ◽  
Ctg Repeat

AbstractExpanded CAG/CTG repeats underlie thirteen neurological disorders, including myotonic dystrophy (DM1) and Huntington’s disease (HD). Upon expansion, CAG/CTG repeat loci acquire heterochromatic characteristics. This observation raises the hypothesis that repeat expansion provokes changes to higher order chromatin folding and thereby affects both gene expression in cis and the genetic instability of the repeat tract. Here we tested this hypothesis directly by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD patient-derived cells. Surprisingly, chromatin contacts remain unchanged upon repeat expansion at both loci. This was true for loci with different DNA methylation levels and CTCF binding. Repeat sizes ranging from 15 to 1,700 displayed strikingly similar chromatin interaction profiles. Our findings argue that extensive changes in heterochromatic properties are not enough to alter chromatin folding at expanded CAG/CTG repeat loci. Moreover, the ectopic insertion of an expanded repeat tract did not change three-dimensional chromatin contacts. We conclude that expanded CAG/CTG repeats have little to no effect on chromatin conformation.

scholarly journals Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

2020 ◽  
Vol 6 (27) ◽  
pp. eaaz4012 ◽  
Author(s):  
Gustavo A. Ruiz Buendía ◽  
Marion Leleu ◽  
Flavia Marzetta ◽  
Ludovica Vanzan ◽  
Jennifer Y. Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Three Dimensional ◽  
Cag Repeat ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Chromatin Conformation ◽  
Repeat Instability ◽  
Ctg Repeats ◽  
Chromatin Interactions ◽  
Ctg Repeat

Expanded CAG/CTG repeats underlie 13 neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD). Upon expansion, disease loci acquire heterochromatic characteristics, which may provoke changes to chromatin conformation and thereby affect both gene expression and repeat instability. Here, we tested this hypothesis by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD–derived cells. We find that allele sizes ranging from 15 to 1700 repeats displayed similar chromatin interaction profiles. This was true for both loci and for alleles with different DNA methylation levels and CTCF binding. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change the conformation of the surrounding chromatin. We conclude that CAG/CTG repeat expansions are not enough to alter chromatin conformation in cis. Therefore, it is unlikely that changes in chromatin interactions drive repeat instability or changes in gene expression in these disorders.

scholarly journals multiHiCcompare: joint normalization and comparative analysis of complex Hi-C experiments

2019 ◽  
Vol 35 (17) ◽  
pp. 2916-2923 ◽  
Author(s):  
John C Stansfield ◽  
Kellen G Cresswell ◽  
Mikhail G Dozmorov
Keyword(s):  
Comparative Analysis ◽  
A Priori ◽  
Three Dimensional ◽  
R Package ◽  
Supplementary Information ◽  
Chromatin Interaction ◽  
Model Framework ◽  
Chromatin Interactions ◽  
Loess Regression ◽  
Sequencing Studies

Abstract Motivation With the development of chromatin conformation capture technology and its high-throughput derivative Hi-C sequencing, studies of the three-dimensional interactome of the genome that involve multiple Hi-C datasets are becoming available. To account for the technology-driven biases unique to each dataset, there is a distinct need for methods to jointly normalize multiple Hi-C datasets. Previous attempts at removing biases from Hi-C data have made use of techniques which normalize individual Hi-C datasets, or, at best, jointly normalize two datasets. Results Here, we present multiHiCcompare, a cyclic loess regression-based joint normalization technique for removing biases across multiple Hi-C datasets. In contrast to other normalization techniques, it properly handles the Hi-C-specific decay of chromatin interaction frequencies with the increasing distance between interacting regions. multiHiCcompare uses the general linear model framework for comparative analysis of multiple Hi-C datasets, adapted for the Hi-C-specific decay of chromatin interaction frequencies. multiHiCcompare outperforms other methods when detecting a priori known chromatin interaction differences from jointly normalized datasets. Applied to the analysis of auxin-treated versus untreated experiments, and CTCF depletion experiments, multiHiCcompare was able to recover the expected epigenetic and gene expression signatures of loss of chromatin interactions and reveal novel insights. Availability and implementation multiHiCcompare is freely available on GitHub and as a Bioconductor R package https://bioconductor.org/packages/multiHiCcompare. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A super enhancer controls expression and chromatin architecture within the MHC class II locus

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Parimal Majumder ◽  
Joshua T. Lee ◽  
Andrew R. Rahmberg ◽  
Gaurav Kumar ◽  
Tian Mi ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Three Dimensional ◽  
Class Ii ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Mhc Ii ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Cell Type Specific ◽  
Hla Dqa1

Super enhancers (SEs) play critical roles in cell type–specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.

scholarly journals Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Judith Rixt Brouwer ◽  
Aline Huguet ◽  
Annie Nicole ◽  
Arnold Munnich ◽  
Geneviève Gourdon
Keyword(s):  
Transgenic Mice ◽  
Trinucleotide Repeat ◽  
Cpg Methylation ◽  
Chromatin Remodelling ◽  
Ctcf Binding ◽  
Type I ◽  
Repeat Instability ◽  
Ctg Repeats ◽  
Repressive Chromatin ◽  
Ctg Repeat

An expanded CTG-repeat in the 3′ UTR of theDMPKgene is responsible for myotonic dystrophy type I (DM1). Somatic and intergenerational instability cause the disease to become more severe during life and in subsequent generations. Evidence is accumulating that trinucleotide repeat instability and disease progression involve aberrant chromatin dynamics. We explored the chromatin environment in relation to expanded CTG-repeat tracts in hearts from transgenic mice carrying the DM1 locus with different repeat lengths. Using bisulfite sequencing we detected abundant CpG methylation in the regions flanking the expanded CTG-repeat. CpG methylation was postulated to affect CTCF binding but we found that CTCF binding is not affected by CTG-repeat length in our transgenic mice. We detected significantly decreasedDMPKsense andSIX5transcript expression levels in mice with expanded CTG-repeats. Expression of the DM1 antisense transcript was barely affected by CTG-repeat expansion. In line with altered gene expression, ChIP studies revealed a locally less active chromatin conformation around the expanded CTG-repeat, namely, decreased enrichment of active histone mark H3K9/14Ac and increased H3K9Me3 enrichment (repressive chromatin mark). We also observed binding of PCNA around the repeats, a candidate that could launch chromatin remodelling cascades at expanded repeats, ultimately affecting gene transcription and repeat instability.

scholarly journals Loop competition and extrusion model predicts CTCF interaction specificity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wang Xi ◽  
Michael A. Beer
Keyword(s):  
Binding Site ◽  
Critical Role ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Ctcf Binding Site ◽  
Loop Formation ◽  
Critical Determinant ◽  
Frequency Changes ◽  
Transcriptional Gene Regulation

AbstractThree-dimensional chromatin looping interactions play an important role in constraining enhancer–promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer–promoter interactions.

scholarly journals Assessing relationships between chromatin interactions and regulatory genomic activities using the self-organizing map

2020 ◽  
Author(s):  
Timothy Kunz ◽  
Lila Rieber ◽  
Shaun Mahony
Keyword(s):  
Genome Organization ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Interaction Space ◽  
The Self ◽  
Chromatin Interaction ◽  
High Dimensional ◽  
Self Organizing Map ◽  
Two Dimensional ◽  
Chromatin Interactions

ABSTRACTFew existing methods enable the visualization of relationships between regulatory genomic activities and genome organization as captured by Hi-C experimental data. Genome-wide Hi-C datasets are often displayed using “heatmap” matrices, but it is difficult to intuit from these heatmaps which biochemical activities are compartmentalized together. High-dimensional Hi-C data vectors can alternatively be projected onto three-dimensional space using dimensionality reduction techniques. The resulting three-dimensional structures can serve as scaffolds for projecting other forms of genomic information, thereby enabling the exploration of relationships between genome organization and various genome annotations. However, while three-dimensional models are contextually appropriate for chromatin interaction data, some analyses and visualizations may be more intuitively and conveniently performed in two-dimensional space.We present a novel approach to the visualization and analysis of chromatin organization based on the Self-Organizing Map (SOM). The SOM algorithm provides a two-dimensional manifold which adapts to represent the high dimensional chromatin interaction space. The resulting data structure can then be used to assess the relationships between regulatory genomic activities and chromatin interactions. For example, given a set of genomic coordinates corresponding to a given biochemical activity, the degree to which this activity is segregated or compartmentalized in chromatin interaction space can be intuitively visualized on the 2D SOM grid and quantified using Lorenz curve analysis. We demonstrate our approach for exploratory analysis of genome compartmentalization in a high-resolution Hi-C dataset from the human GM12878 cell line. Our SOM-based approach provides an intuitive visualization of the large-scale structure of Hi-C data and serves as a platform for integrative analyses of the relationships between various genomic activities and genome organization.

SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

2009 ◽  
Vol 125 (4) ◽  
pp. 437-444 ◽  
Author(s):  
Yih-Ru Wu ◽  
I-Cheng Chen ◽  
Bing-Wen Soong ◽  
Shih-Huan Kao ◽  
Ghin-Chueh Lee ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Repeat Expansion ◽  
Functional Implications ◽  
Ctg Repeat

scholarly journals DeepC: Predicting chromatin interactions using megabase scaled deep neural networks and transfer learning

2019 ◽  
Author(s):  
Ron Schwessinger ◽  
Matthew Gosden ◽  
Damien Downes ◽  
Richard Brown ◽  
Jelena Telenius ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Large Scale ◽  
Genome Structure ◽  
Chromatin Interaction ◽  
3D Genome ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
Chromatin Folding ◽  
The Impact ◽  
3D Genome Structure

AbstractUnderstanding 3D genome structure requires high throughput, genome-wide approaches. However, assays for all vs. all chromatin interaction mapping are expensive and time consuming, which severely restricts their usage for large-scale mutagenesis screens or for mapping the impact of sequence variants. Computational models sophisticated enough to grasp the determinants of chromatin folding provide a unique window into the functional determinants of 3D genome structure as well as the effects of genome variation.A chromatin interaction predictor should work at the base pair level but also incorporate large-scale genomic context to simultaneously capture the large scale and intricate structures of chromatin architecture. Similarly, to be a flexible and generalisable approach it should also be applicable to data it has not been explicitly trained on. To develop a model with these properties, we designed a deep neuronal network (deepC) that utilizes transfer learning to accurately predict chromatin interactions from DNA sequence at megabase scale. The model generalizes well to unseen chromosomes and works across cell types, Hi-C data resolutions and a range of sequencing depths. DeepC integrates DNA sequence context on an unprecedented scale, bridging the different levels of resolution from base pairs to TADs. We demonstrate how this model allows us to investigate sequence determinants of chromatin folding at genome-wide scale and to predict the importance of regulatory elements and the impact of sequence variations.

scholarly journals Loop extrusion model predicts CTCF interaction specificity

2020 ◽  
Author(s):  
Wang Xi ◽  
Michael A Beer
Keyword(s):  
Binding Site ◽  
Critical Role ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Chromatin Interaction ◽  
Ctcf Binding Site ◽  
Loop Formation ◽  
Critical Determinant ◽  
Frequency Changes ◽  
Transcriptional Gene Regulation

AbstractThree-dimensional chromatin looping interactions play an important role in constraining enhancer-promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer-promoter interactions.

scholarly journals Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach

2021 ◽  
Vol 12 ◽  
Author(s):  
Sambhavi Animesh ◽  
Ruchi Choudhary ◽  
Bertrand Jern Han Wong ◽  
Charlotte Tze Jia Koh ◽  
Xin Yi Ng ◽  
...  
Keyword(s):  
Genome Organization ◽  
Needle Biopsy ◽  
Nasopharyngeal Cancer ◽  
Three Dimensional ◽  
Chromatin Interaction ◽  
Solid Cancer ◽  
3D Genome ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Topologically Associated Domains

Nasopharyngeal cancer (NPC), a cancer derived from epithelial cells in the nasopharynx, is a cancer common in China, Southeast Asia, and Africa. The three-dimensional (3D) genome organization of nasopharyngeal cancer is poorly understood. A major challenge in understanding the 3D genome organization of cancer samples is the lack of a method for the characterization of chromatin interactions in solid cancer needle biopsy samples. Here, we developed Biop-C, a modified in situ Hi-C method using solid cancer needle biopsy samples. We applied Biop-C to characterize three nasopharyngeal cancer solid cancer needle biopsy patient samples. We identified topologically associated domains (TADs), chromatin interaction loops, and frequently interacting regions (FIREs) at key oncogenes in nasopharyngeal cancer from the Biop-C heatmaps. We observed that the genomic features are shared at some important oncogenes, but the patients also display extensive heterogeneity at certain genomic loci. On analyzing the super enhancer landscape in nasopharyngeal cancer cell lines, we found that the super enhancers are associated with FIREs and can be linked to distal genes via chromatin loops in NPC. Taken together, our results demonstrate the utility of our Biop-C method in investigating 3D genome organization in solid cancers.

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