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 3D Genome Structure Variation Across Cell Types Captured by Integrating Multi-omics

2019 ◽  
Author(s):  
Yang Xu ◽  
Tongye Shen ◽  
Rachel Patton McCord
Keyword(s):  
Chromosome Structure ◽  
Single Cells ◽  
Genome Structure ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Cell Identity ◽  
Histone Marks ◽  
3D Genome ◽  
The Impact ◽  
3D Genome Structure

AbstractBackground3D genome structure contributes to the establishment or maintenance of cell identity in part by organizing genes into spatial active or inactive compartments. Less is known about how compartment switching occurs across different cell types. Rather than analyze individual A/B compartment switches between pairs of cell types, here, we seek to identify coordinated changes in groups of compartment-scale interactions across a spectrum of cell types.ResultsTo characterize the impact of genome folding on cell identity, we integrated 35 Hi-C datasets with 125 DNase-seq, 244 RNA-seq, and 893 ChIP-seq datasets. We first find physical associations with the nuclear lamina inform the most dramatic changes in chromosome structure across cell types. By examining variations in chromosome structure, transcription, and chromatin accessibility, we further observe that certain sets of correlated chromosome structure contacts also co-vary in transcription and chromatin accessibility. Analyzing ChIP-seq signals, we find that sets of chromosome contacts that form and break in sync tend to share active or suppressive histone marks. Finally, we observe that similar principles appear to govern chromosome structure fluctuations across single cells as were found across cell types.ConclusionOur results suggest that cells adapt their chromosome structures, guided by variable associations with the lamina and histone marks, to allocate up-regulatory or down-regulatory resources to certain regions and achieve transcription and chromatin accessibility variation. Our study shows E-PCA can identify the major variable interaction sets within populations of single cells, across broad categories of normal cell types, and between cancer and non-cancerous cell types.

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

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 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 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 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

scholarly journals Radiation-induced DNA damage and repair effects on 3D genome organization

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacob T. Sanders ◽  
Trevor F. Freeman ◽  
Yang Xu ◽  
Rosela Golloshi ◽  
Mary A. Stallard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Expression Regulation ◽  
Genome Structure ◽  
Cell Types ◽  
Dimensional Structure ◽  
X Rays ◽  
3D Genome ◽  
Radiation Induced ◽  
The Impact ◽  
3D Genome Structure

AbstractThe three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. We irradiate fibroblasts, lymphoblasts, and ATM-deficient fibroblasts with 5 Gy X-rays and perform Hi-C at 30 minutes, 24 hours, or 5 days after irradiation. We observe that 3D genome changes after irradiation are cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.

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

2020 ◽  
Author(s):  
Tejaswi Iyyanki ◽  
Baozhen Zhang ◽  
Qiushi Jin ◽  
Hongbo Yang ◽  
Tingting Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cell ◽  
Genome Structure ◽  
Epigenetic Mechanism ◽  
Open Chromatin ◽  
3D Genome ◽  
Genome Wide ◽  
Specific Regulation ◽  
And Migration ◽  
3D Genome Structure

AbstractMuscle-invasive bladder cancers have recently been 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. For example, FOXA1, GATA3, and PPARG have been shown to be essential for luminal subtype-specific regulation and subtype switching, while TP63 and STAT3 are critical for basal subtype bladder cancer. Despite these advances, the underlying epigenetic mechanism and 3D chromatin architecture for subtype-specific regulation in bladder cancers remains largely unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, TF binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we mapped genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors, for the first time in bladder cancer. We showed that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other luminal-specific genes (such as FOXA1, GATA3, and PPARG) and affects cancer cell proliferation and migration. In summary, our work shows a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggested a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype.

scholarly journals Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure

2020 ◽  
Author(s):  
Noha Osman ◽  
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

AbstractNumerous 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. 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. 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.

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