scholarly journals Seeing the forest through the trees: prioritising potentially functional interactions from Hi-C

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ning Liu ◽  
Wai Yee Low ◽  
Hamid Alinejad-Rokny ◽  
Stephen Pederson ◽  
Timothy Sadlon ◽  
...  
Keyword(s):  
Dimensional Space ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Valuable Insight ◽  
Gene Promoters ◽  
Chromosome Conformation ◽  
Functional Interactions ◽  
Topologically Associated Domains ◽  
Downstream Analysis ◽  
Drive Gene

AbstractEukaryotic genomes are highly organised within the nucleus of a cell, allowing widely dispersed regulatory elements such as enhancers to interact with gene promoters through physical contacts in three-dimensional space. Recent chromosome conformation capture methodologies such as Hi-C have enabled the analysis of interacting regions of the genome providing a valuable insight into the three-dimensional organisation of the chromatin in the nucleus, including chromosome compartmentalisation and gene expression. Complicating the analysis of Hi-C data, however, is the massive amount of identified interactions, many of which do not directly drive gene function, thus hindering the identification of potentially biologically functional 3D interactions. In this review, we collate and examine the downstream analysis of Hi-C data with particular focus on methods that prioritise potentially functional interactions. We classify three groups of approaches: structural-based discovery methods, e.g. A/B compartments and topologically associated domains, detection of statistically significant chromatin interactions, and the use of epigenomic data integration to narrow down useful interaction information. Careful use of these three approaches is crucial to successfully identifying potentially functional interactions within the genome.

scholarly journals Seeing the forest through the trees: Identifying functional interactions from Hi-C

2020 ◽  
Author(s):  
Ning Liu ◽  
Wai Yee Low ◽  
Hamid Alinejad-Rokny ◽  
Stephen Pederson ◽  
Timothy Sadlon ◽  
...  
Keyword(s):  
Dimensional Space ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Valuable Insight ◽  
Gene Promoters ◽  
Chromosome Conformation ◽  
Functional Interactions ◽  
Domain Discovery ◽  
Downstream Analysis ◽  
Drive Gene

AbstractEukaryotic genomes are highly organised within the nucleus of a cell, allowing widely dispersed regulatory elements such as enhancers to interact with gene promoters through physical contacts in three-dimensional space. Recent chromosome conformation capture methodologies such as Hi-C have enabled the analysis of interacting regions of the genome providing a valuable insight into the three-dimensional organisation of the chromatin in the nucleus, including chromosome compartmentalisation and gene expression. Complicating the analysis of Hi-C data however is the massive amount of identified interactions, many of which do not directly drive gene function, thus hindering the identification of potentially biologically functional 3D interactions. In this review, we collate and examine the downstream analysis of Hi-C data with particular focus on methods that identify significant functional interactions. We classify three groups of approaches; structurally-associated domain discovery methods e.g. topologically-associated domains and compartments, detection of statistically significant interactions via background models, and the use of epigenomic data integration to identify functional interactions. Careful use of these three approaches is crucial to successfully identifying functional interactions within the genome.

scholarly journals Spatial organization of transcript elongation and splicing kinetics

2021 ◽  
Author(s):  
Alyssa D. Casill ◽  
Adam J. Haimowitz ◽  
Brian Kosmyna ◽  
Charles C. Query ◽  
Kenny Ye ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Spatial Organization ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Multiple Control ◽  
Pol Ii ◽  
Topologically Associated Domains ◽  
Transcript Elongation ◽  
Kinetics Of

SummaryThe organization of the genome in three-dimensional space has been shown to play an important role in gene expression. Specifically, facets of genomic interaction such as topologically associated domains (TADs) have been shown to regulate transcription by bringing regulatory elements into close proximity1. mRNA production is an intricate process with multiple control points including regulation of Pol II elongation and the removal of non-coding sequences via pre-mRNA splicing2. The connection between genomic compartments and the kinetics of RNA biogenesis and processing has been largely unexplored. Here, we measure Pol II elongation and splicing kinetics genome-wide using a novel technique that couples nascent RNA-seq with a mathematical model of transcription and co-transcriptional RNA processing. We uncovered multiple layers of spatial organization of these rates: the rate of splicing is coordinated across introns within individual genes, and both elongation and splicing rates are coordinated within TADs, as are alternative splicing outcomes. Overall, our work establishes that the kinetics of transcription and splicing are coordinated by the spatial organization of the genome and suggests that TADs are a major platform for coordination of alternative splicing.

scholarly journals EPCO-31. EPIGENOMIC INTRATUMORAL HETEROGENEITY OF GLIOBLASTOMA IN THREE-DIMENSIONAL SPACE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii76-ii76
Author(s):  
Radhika Mathur ◽  
Sriranga Iyyanki ◽  
Stephanie Hilz ◽  
Chibo Hong ◽  
Joanna Phillips ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Spatial Location ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Intratumoral Heterogeneity ◽  
Tumor Evolution ◽  
Open Chromatin

Abstract Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and generation of therapy-resistant clones. While ITH in glioblastoma has been well-characterized at the genomic and transcriptomic levels, the extent of ITH at the epigenomic level and its biological and clinical significance are not well understood. In collaboration with neurosurgeons, neuropathologists, and biomedical imaging experts, we have established a novel topographical approach towards characterizing epigenomic ITH in three-dimensional (3-D) space. We utilize pre-operative MRI scans to define tumor volume and then utilize 3-D surgical neuro-navigation to intra-operatively acquire 10+ samples representing maximal anatomical diversity. The precise spatial location of each sample is mapped by 3-D coordinates, enabling tumors to be visualized in 360-degrees and providing unprecedented insight into their spatial organization and patterning. For each sample, we conduct assay for transposase-accessible chromatin using sequencing (ATAC-Seq), which provides information on the genomic locations of open chromatin, DNA-binding proteins, and individual nucleosomes at nucleotide resolution. We additionally conduct whole-exome sequencing and RNA sequencing for each spatially mapped sample. Integrative analysis of these datasets reveals distinct patterns of chromatin accessibility within glioblastoma tumors, as well as their associations with genetically defined clonal expansions. Our analysis further reveals how differences in chromatin accessibility within tumors reflect underlying transcription factor activity at gene regulatory elements, including both promoters and enhancers, and drive expression of particular gene expression sets, including neuronal and immune programs. Collectively, this work provides the most comprehensive characterization of epigenomic ITH to date, establishing its importance for driving tumor evolution and therapy resistance in glioblastoma. As a resource for further investigation, we have provided our datasets on an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.

Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Harri Makkonen ◽  
Jorma J. Palvimo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Binding Sites ◽  
Target Genes ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Gene Promoters ◽  
Loop Formation ◽  
Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

scholarly journals Reorganization of chromosome architecture in replicative cellular senescence

2016 ◽  
Vol 2 (2) ◽  
pp. e1500882 ◽  
Author(s):  
Steven W. Criscione ◽  
Marco De Cecco ◽  
Benjamin Siranosian ◽  
Yue Zhang ◽  
Jill A. Kreiling ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Structural Model ◽  
Three Dimensional ◽  
Chromatin Accessibility ◽  
Genome Chromosome ◽  
Chromosome Conformation ◽  
Topologically Associated Domains ◽  
Chromosomal Architecture ◽  
Fundamental Biological Process ◽  
3D Architecture

Replicative cellular senescence is a fundamental biological process characterized by an irreversible arrest of proliferation. Senescent cells accumulate a variety of epigenetic changes, but the three-dimensional (3D) organization of their chromatin is not known. We applied a combination of whole-genome chromosome conformation capture (Hi-C), fluorescence in situ hybridization, and in silico modeling methods to characterize the 3D architecture of interphase chromosomes in proliferating, quiescent, and senescent cells. Although the overall organization of the chromatin into active (A) and repressive (B) compartments and topologically associated domains (TADs) is conserved between the three conditions, a subset of TADs switches between compartments. On a global level, the Hi-C interaction matrices of senescent cells are characterized by a relative loss of long-range and gain of short-range interactions within chromosomes. Direct measurements of distances between genetic loci, chromosome volumes, and chromatin accessibility suggest that the Hi-C interaction changes are caused by a significant reduction of the volumes occupied by individual chromosome arms. In contrast, centromeres oppose this overall compaction trend and increase in volume. The structural model arising from our study provides a unique high-resolution view of the complex chromosomal architecture in senescent cells.

scholarly journals The DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 289 ◽  
Author(s):  
Ping Hong ◽  
Hao Jiang ◽  
Weize Xu ◽  
Da Lin ◽  
Qian Xu ◽  
...  
Keyword(s):  
Target Genes ◽  
High Efficiency ◽  
New Technology ◽  
Three Dimensional ◽  
Large Data ◽  
Regulatory Elements ◽  
Chromosome Conformation Capture ◽  
Genome Chromosome ◽  
Chromosome Conformation ◽  
3D Genome

It is becoming increasingly important to understand the mechanism of regulatory elements on target genes in long-range genomic distance. 3C (chromosome conformation capture) and its derived methods are now widely applied to investigate three-dimensional (3D) genome organizations and gene regulation. Digestion-ligation-only Hi-C (DLO Hi-C) is a new technology with high efficiency and cost-effectiveness for whole-genome chromosome conformation capture. Here, we introduce the DLO Hi-C tool, a flexible and versatile pipeline for processing DLO Hi-C data from raw sequencing reads to normalized contact maps and for providing quality controls for different steps. It includes more efficient iterative mapping and linker filtering. We applied the DLO Hi-C tool to different DLO Hi-C datasets and demonstrated its ability in processing large data with multithreading. The DLO Hi-C tool is suitable for processing DLO Hi-C and in situ DLO Hi-C datasets. It is convenient and efficient for DLO Hi-C data processing.

scholarly journals Two independent modes of chromosome organization are revealed by cohesin removal

2016 ◽  
Author(s):  
Wibke Schwarzer ◽  
Nezar Abdennur ◽  
Anton Goloborodko ◽  
Aleksandra Pekowska ◽  
Geoffrey Fudenberg ◽  
...  
Keyword(s):  
Specific Activity ◽  
Three Dimensional ◽  
Regulatory Elements ◽  
Chromosome Organization ◽  
Chromosome Conformation ◽  
Genome Reorganization ◽  
Independent Segregation ◽  
Architectural Proteins ◽  
Transcriptional Changes ◽  
Extrusion Mechanism

The three-dimensional organization of chromosomes is tightly related to their biological function 1. Both imaging and chromosome conformation capture studies have revealed several layers of organization 2-4: segregation into active and inactive compartments at the megabase scale 5, and partitioning into domains (TADs) 6,7 and associated loops 8 at the sub-megabase scale. Yet, it remains unclear how these layers of genome organization form, interact with one another, and contribute to or result from genome activities. TADs seem to have critical roles in regulating gene expression by promoting or preventing interactions between promoters and distant cis-acting regulatory elements 9-14, and different architectural proteins, including cohesin, have been proposed to play central roles in their formation 15,16. However, experimental depletions of these proteins have resulted in marginal changes in chromosome organization 17-19. Here, we show that deletion of the cohesin-loading factor, Nipbl, leads to loss of chromosome-associated cohesin and results in dramatic genome reorganization. TADs and associated loops vanish globally, even in the absence of transcriptional changes. In contrast, segregation into compartments is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the independent action of two distinct mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartment regions, defined by the underlying chromatin state; and 2) cohes-dependent formation of TADs possibly by the recently proposed loop extrusion mechanism 20,21, enabling long-range and target-specific activity of promiscuous enhancers. The interplay between these mechanisms creates an architecture that is more complex than a simple hierarchy of layers and can be central to guiding normal development.

scholarly journals Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes

2019 ◽  
Author(s):  
Jennifer M. Luppino ◽  
Daniel S. Park ◽  
Son C. Nguyen ◽  
Yemin Lan ◽  
Zhuxuan Xu ◽  
...  
Keyword(s):  
Mechanistic Explanation ◽  
Regulatory Elements ◽  
Chromosome Conformation ◽  
Regulatory Domains ◽  
Domain Interactions ◽  
Topologically Associated Domains ◽  
Self Association ◽  
Cornelia De Lange ◽  
Transcriptional Bursting ◽  
And Function

AbstractThe mammalian genome can be segmented into thousands of topologically associated domains (TADs) based on chromosome conformation capture studies, such as Hi-C. TADs have been proposed to act as insulated neighborhoods, spatially sequestering and insulating the enclosed genes and regulatory elements through chromatin looping and self-association. Recent results indicate that inter-TAD interactions can also occur, suggesting boundaries may be semi-permissible. However, the nature, extent, and function, if any, of these inter-TAD interactions remains unclear. Here, we combine super-and high-resolution microscopy with Oligopaint technology to precisely quantify the interaction frequency within and between neighboring domains in human cells. We find that intermingling across domain boundaries is a widespread feature of the human genome, with varying levels of interactions across different loci that correlate with their differing boundary strengths by Hi-C. Moreover, we find that cohesin depletion, which is known to abolish TADs at the population-average level, does not induce ectopic interactions but instead reduces both intra- and inter-domain interactions to a similar extent. Reduced chromatin intermixing due to cohesin loss affects domain incorporation and transcriptional bursting frequencies of genes close to architectural boundaries, potentially explaining the gene expression changes observed in the cohesinopathy Cornelia de Lange syndrome. Together, our results provide a mechanistic explanation for stochastic domain intermingling, arguing that cohesin partially bypasses boundaries to promote alternating incorporation of boundary-proximal genes into neighboring regulatory domains.

scholarly journals Three-Dimensional Genome Organization in Breast and Gynecological Cancers: How Chromatin Folding Influences Tumorigenic Transcriptional Programs

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 75
Author(s):  
Stephanie I. Nuñez-Olvera ◽  
Jonathan Puente-Rivera ◽  
Rosalio Ramos-Payán ◽  
Carlos Pérez-Plasencia ◽  
Yarely M. Salinas-Vera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Function ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Gene Promoters ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rnas ◽  
Insulator Elements

A growing body of research on the transcriptome and cancer genome has demonstrated that many gynecological tumor-specific gene mutations are located in cis-regulatory elements. Through chromosomal looping, cis-regulatory elements interact which each other to control gene expression by bringing distant regulatory elements, such as enhancers and insulators, into close proximity with promoters. It is well known that chromatin connections may be disrupted in cancer cells, promoting transcriptional dysregulation and the expression of abnormal tumor suppressor genes and oncogenes. In this review, we examine the roles of alterations in 3D chromatin interactions. This includes changes in CTCF protein function, cancer-risk single nucleotide polymorphisms, viral integration, and hormonal response as part of the mechanisms that lead to the acquisition of enhancers or super-enhancers. The translocation of existing enhancers, as well as enhancer loss or acquisition of insulator elements that interact with gene promoters, is also revised. Remarkably, similar processes that modify 3D chromatin contacts in gene promoters may also influence the expression of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), which have emerged as key regulators of gene expression in a variety of cancers, including gynecological malignancies.

scholarly journals Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Jonas Paulsen ◽  
Monika Sekelja ◽  
Anja R. Oldenburg ◽  
Alice Barateau ◽  
Nolwenn Briand ◽  
...  
Keyword(s):  
Single Cells ◽  
Nuclear Periphery ◽  
Three Dimensional ◽  
Modeling Framework ◽  
Chromosome Conformation ◽  
3D Genome ◽  
Spatial Features ◽  
Nuclear Lamin ◽  
Topologically Associated Domains ◽  
User Friendly

Abstract Current three-dimensional (3D) genome modeling platforms are limited by their inability to account for radial placement of loci in the nucleus. We present Chrom3D, a user-friendly whole-genome 3D computational modeling framework that simulates positions of topologically-associated domains (TADs) relative to each other and to the nuclear periphery. Chrom3D integrates chromosome conformation capture (Hi-C) and lamin-associated domain (LAD) datasets to generate structure ensembles that recapitulate radial distributions of TADs detected in single cells. Chrom3D reveals unexpected spatial features of LAD regulation in cells from patients with a laminopathy-causing lamin mutation. Chrom3D is freely available on github.

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