scholarly journals Mining 3D genome structure populations identifies major factors governing the stability of regulatory communities

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Chao Dai ◽  
Wenyuan Li ◽  
Harianto Tjong ◽  
Shengli Hao ◽  
Yonggang Zhou ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Genome Structure ◽  
Protein Structures ◽  
Three Dimensional ◽  
Expression Variability ◽  
3D Genome ◽  
Significant Challenge ◽  
The Stability ◽  
Major Factors ◽  
3D Genome Structure

Abstract Three-dimensional (3D) genome structures vary from cell to cell even in an isogenic sample. Unlike protein structures, genome structures are highly plastic, posing a significant challenge for structure-function mapping. Here we report an approach to comprehensively identify 3D chromatin clusters that each occurs frequently across a population of genome structures, either deconvoluted from ensemble-averaged Hi-C data or from a collection of single-cell Hi-C data. Applying our method to a population of genome structures (at the macrodomain resolution) of lymphoblastoid cells, we identify an atlas of stable inter-chromosomal chromatin clusters. A large number of these clusters are enriched in binding of specific regulatory factors and are therefore defined as ‘Regulatory Communities.’ We reveal two major factors, centromere clustering and transcription factor binding, which significantly stabilize such communities. Finally, we show that the regulatory communities differ substantially from cell to cell, indicating that expression variability could be impacted by genome structures.

scholarly journals Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tejaswi Iyyanki ◽  
Baozhen Zhang ◽  
Qixuan Wang ◽  
Ye Hou ◽  
Qiushi Jin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Cancer Cell ◽  
Genome Structure ◽  
Transcription Factor Binding ◽  
Specific Gene ◽  
Open Chromatin ◽  
Factor Binding ◽  
3D Genome ◽  
Genome Wide

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

Hi-CO: 3D genome structure analysis with nucleosome resolution

2021 ◽  
Author(s):  
Masae Ohno ◽  
Tadashi Ando ◽  
David G. Priest ◽  
Yuichi Taniguchi
Keyword(s):  
Structure Analysis ◽  
Genome Structure ◽  
3D Genome ◽  
3D Genome Structure

Factors affecting the amplitude of the τ angle in proteins: a revisitation

2017 ◽  
Vol 73 (7) ◽  
pp. 618-625 ◽  
Author(s):  
Nicole Balasco ◽  
Luciana Esposito ◽  
Luigi Vitagliano
Keyword(s):  
Protein Structures ◽  
Factors Affecting ◽  
X Ray ◽  
Backbone Conformation ◽  
Potential Factors ◽  
The Stability ◽  
Major Factors ◽  
The Impact ◽  
Open Issues

The protein folded state is the result of the fine balance of a variety of different forces. Even minor structural perturbations may have a significant impact on the stability of these macromolecules. Studies carried out in recent decades have led to the convergent view that proteins are endowed with a flexible spine. One of the open issues related to protein local backbone geometry is the identification of the factors that influence the amplitude of the τ (N—Cα—C) angle. Here, statistical analyses performed on an updated ensemble of X-ray protein structures by dissecting the contribution of the major factors that can potentially influence the local backbone geometry of proteins are reported. The data clearly indicate that the local backbone conformation has a prominent impact on the modulation of the τ angle. Therefore, a proper assessment of the impact of the other potential factors can only be appropriately evaluated when small (φ, ψ) regions are considered. Here, it is shown that when the contribution of the backbone conformation is removed by considering small (φ, ψ) areas, an impact of secondary structure, as defined byDSSP, and/or the residue type on τ is still detectable, although to a limited extent. Indeed, distinct τ-value distributions are detected for Pro/Gly and β-branched (Ile/Val) residues. The key role of the local backbone conformation highlighted here supports the use of variable local backbone geometry in protein refinement protocols.

scholarly journals Repeat elements organise 3D genome structure and mediate transcription in the filamentous fungus Epichloë festucae

PLoS Genetics ◽  
2018 ◽  
Vol 14 (10) ◽  
pp. e1007467 ◽  
Author(s):  
David J. Winter ◽  
Austen R. D. Ganley ◽  
Carolyn A. Young ◽  
Ivan Liachko ◽  
Christopher L. Schardl ◽  
...  
Keyword(s):  
Filamentous Fungus ◽  
Genome Structure ◽  
Repeat Elements ◽  
3D Genome ◽  
Epichloë Festucae ◽  
3D Genome Structure

scholarly journals Repeat elements organize 3D genome structure and mediate transcription in the filamentous fungusEpichloë festucae

2018 ◽  
Author(s):  
David J Winter ◽  
Austen RD Ganley ◽  
Carolyn A Young ◽  
Ivan Liachko ◽  
Christopher L Schardl ◽  
...  
Keyword(s):  
Genome Structure ◽  
Regulation Of Gene Expression ◽  
Three Dimensional ◽  
Structural Features ◽  
Dimensional Structure ◽  
In Planta ◽  
Repeat Elements ◽  
Symbiotic Relationships ◽  
3D Genome ◽  
Transcriptional Changes

AbstractStructural features of genomes, including the three-dimensional arrangement of DNA in the nucleus, are increasingly seen as key contributors to the regulation of gene expression. However, studies on how genome structure and nuclear organization influence transcription have so far been limited to a handful of model species. This narrow focus limits our ability to draw general conclusions about the ways in which three-dimensional structures are encoded, and to integrate information from three-dimensional data to address a broader gamut of biological questions. Here, we generate a complete and gapless genome sequence for the filamentous fungus,Epichloë festucae. Coupling it with RNAseq and HiC data, we investigate how the structure of the genome contributes to the suite of transcriptional changes that anEpichloëspecies needs to maintain symbiotic relationships with its grass host. Our results reveal a unique “patchwork” genome, in which repeat-rich blocks of DNA with discrete boundaries are interspersed by gene-rich sequences. In contrast to other species, the three-dimensional structure of the genome is anchored by these repeat blocks, which act to isolate transcription in neighbouring gene-rich regions. Genes that are differentially expressed in planta are enriched near the boundaries of these repeat-rich blocks, suggesting that their three-dimensional orientation partly encodes and regulates the symbiotic relationship formed by this organism.

scholarly journals Modification of Nuclear Compartments and the 3D Genome in the Course of a Viral Infection

Acta Naturae ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 34-46
Author(s):  
S. V. Razin ◽  
A. A. Gavrilov ◽  
O. V. Iarovaia
Keyword(s):  
Viral Infection ◽  
Cell Nucleus ◽  
Genome Structure ◽  
Antiviral Defense ◽  
3D Genome ◽  
Nuclear Compartments ◽  
Defense Systems ◽  
3D Genome Structure ◽  
Cellular Genome

The review addresses the question of how the structural and functional compartmentalization of the cell nucleus and the 3D organization of the cellular genome are modified during the infection of cells with various viruses. Particular attention is paid to the role of the introduced changes in the implementation of the viral strategy to evade the antiviral defense systems and provide conditions for viral replication. The discussion focuses on viruses replicating in the cell nucleus. Cytoplasmic viruses are mentioned in cases when a significant reorganization of the nuclear compartments or the 3D genome structure occurs during an infection with these viruses.

scholarly journals GEM: A manifold learning based framework for reconstructing spatial organizations of chromosomes

2017 ◽  
Author(s):  
Guangxiang Zhu ◽  
Wenxuan Deng ◽  
Hailin Hu ◽  
Rui Ma ◽  
Sai Zhang ◽  
...  
Keyword(s):  
Manifold Learning ◽  
Learning Strategy ◽  
Genome Structure ◽  
Three Dimensional ◽  
Conformational Energy ◽  
3D Genome ◽  
Learning Framework ◽  
Reconstruction Methods ◽  
Eukaryotic Gene ◽  
Validation Tests

AbstractDecoding the spatial organizations of chromosomes has crucial implications for studying eukaryotic gene regulation. Recently, Chromosomal conformation capture based technologies, such as Hi-C, have been widely used to uncover the interaction frequencies of genomic loci in high-throughput and genome-wide manner and provide new insights into the folding of three-dimensional (3D) genome structure. In this paper, we develop a novel manifold learning framework, called GEM (Genomic organization reconstructor based on conformational Energy and Manifold learning), to elucidate the underlying 3D spatial organizations of chromosomes from Hi-C data. Unlike previous chromatin structure reconstruction methods, which explicitly assume specific relationships between Hi-C interaction frequencies and spatial distances between distal genomic loci, GEM is able to reconstruct an ensemble of chromatin conformations by directly embedding the neigh-boring affinities from Hi-C space into 3D Euclidean space based on a manifold learning strategy that considers both the fitness of Hi-C data and the biophysical feasibility of the modeled structures, which are measured by the conformational energy derived from our current biophysical knowledge about the 3D polymer model. Extensive validation tests on both simulated interaction frequency data and experimental Hi-C data of yeast and human demonstrated that GEM not only greatly outperformed other state-of-art modeling methods but also reconstructed accurate chromatin structures that agreed well with the hold-out or independent Hi-C data and sparse geometric restraints derived from the previous fluorescence in situ hybridization (FISH) studies. In addition, as GEM can generate accurate spatial organizations of chromosomes by integrating both experimentally-derived spatial contacts and conformational energy, we for the first time extended our modeling method to recover long-range genomic interactions that are missing from the original Hi-C data. All these results indicated that GEM can provide a physically and physiologically valid 3D representations of the organizations of chromosomes and thus serve as an effective and useful genome structure reconstructor.

scholarly journals Exploring the Effects of Genetic Variation on Gene Regulation in Cancer in the Context of 3D Genome Structure

2021 ◽  
Author(s):  
Noha Osman ◽  
Abd-El-Monsif Shawky ◽  
Michal Brylinski
Keyword(s):  
High Risk ◽  
Genetic Variants ◽  
Large Scale ◽  
Target Genes ◽  
Genome Structure ◽  
Regulatory Elements ◽  
3D Genome ◽  
Risk Snps ◽  
Prostate Cancers ◽  
3D Genome Structure

Abstract Background: Numerous genome-wide association studies (GWAS) conducted to date revealed genetic variants associated with various diseases, including breast and prostate cancers. Despite the availability of these large-scale data, relatively few variants have been functionally characterized, mainly because the majority of single-nucleotide polymorphisms (SNPs) map to the non-coding regions of the human genome. The functional characterization of these non-coding variants and the identification of their target genes remain challenging.Results: In this communication, we explore the potential functional mechanisms of non-coding SNPs by integrating GWAS with the high-resolution chromosome conformation capture (Hi-C) data for breast and prostate cancers. We show that more genetic variants map to regulatory elements through the 3D genome structure than the 1D linear genome lacking physical chromatin interactions. Importantly, the association of enhancers, transcription factors, and their target genes with breast and prostate cancers tends to be higher when these regulatory elements are mapped to high-risk SNPs through spatial interactions compared to simply using a linear proximity. Finally, we demonstrate that topologically associating domains (TADs) carrying high-risk SNPs also contain gene regulatory elements whose association with cancer is generally higher than those belonging to control TADs containing no high-risk variants.Conclusions: Our results suggest that many SNPs may contribute to the cancer development by affecting the expression of certain tumor-related genes through long-range chromatin interactions with gene regulatory elements. Integrating large-scale genetic datasets with the 3D genome structure offers an attractive and unique approach to systematically investigate the functional mechanisms of genetic variants in disease risk and progression.

scholarly journals Constricted migration is associated with stable 3D genome structure differences in melanoma cells

2019 ◽  
Author(s):  
Rosela Golloshi ◽  
Trevor F. Freeman ◽  
Priyojit Das ◽  
Thomas Isaac Raines ◽  
Rebeca San Martin ◽  
...  
Keyword(s):  
Chromosome Structure ◽  
Metastatic Cancer ◽  
Genome Structure ◽  
Collagen Matrix ◽  
Phenotypic Differences ◽  
3D Genome ◽  
Expression Of Genes ◽  
Structure Changes ◽  
3D Genome Structure ◽  
Nuclear Deformations

AbstractTo spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation and DNA repair, here we investigate how confined migration affects or is affected by 3D genome structure. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration. These cells display a stably higher migration efficiency, elongated morphology, and differences in the distribution of Lamin A/C and heterochromatin. Using Hi-C, we observe differences in chromosome spatial compartmentalization specific to cells that have passed through constrictions and related alterations in expression of genes associated with migration and metastasis. These sequentially constricted cells also show more nuclear deformations and altered behavior in a 3D collagen matrix. Our observations reveal a relationship between chromosome structure changes, metastatic gene signatures, and the altered nuclear appearance of aggressive melanoma.

scholarly journals Experience-independent transformation of single-cell 3D genome structure and transcriptome during postnatal development of the mammalian brain

2020 ◽  
Author(s):  
Longzhi Tan ◽  
Wenping Ma ◽  
Honggui Wu ◽  
Yinghui Zheng ◽  
Dong Xing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Genome Structure ◽  
Sensory Experience ◽  
Mammalian Genome ◽  
Brain Cells ◽  
List Type ◽  
3D Genome ◽  
Allele Specific ◽  
3D Genome Structure

SUMMARYBoth transcription and 3D organization of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome structures of single brain cells have not been solved; little is known about the dynamics of single-cell transcriptome and 3D genome after birth. Here we generate a transcriptome atlas of 3,517 cells and a 3D genome atlas of 3,646 cells from the developing mouse cortex and hippocampus, using our high-resolution MALBAC-DT and Dip-C methods. In adults, 3D genome “structure types” delineate all major cell types, with high correlation between A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first postnatal month. In neurons, 3D genome is rewired across multiple scales, correlated with gene expression modules and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome-wide differences. These findings uncover a previously unknown dimension of neurodevelopment.HIGHLIGHTSTranscriptomes and 3D genome structures of single brain cells (both neurons and glia) in the developing mouse forebrainCell type identity encoded in the 3D wiring of the mammalian genome (“structure types”)Major transformation of both transcriptome and 3D genome during the first month of life, independent of sensory experienceAllele-specific 3D structure at 7 imprinted gene loci, including one that spans a whole chromosome

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