scholarly journals The order of macrophage 4D genome coordinates gene transcription during differentiation and infection

2021 ◽  
Author(s):  
Gang Cao ◽  
Da Lin ◽  
Weize Xu ◽  
Ping Hong ◽  
Chengchao Wu ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Genome Organization ◽  
Target Genes ◽  
Three Dimensional ◽  
Drug Candidate ◽  
Genome Architecture ◽  
Chromatin Conformation ◽  
Chromatin Loop ◽  
Target Genome ◽  
Organizational Patterns

Abstract The highly organized three-dimensional genome is crucial for gene transcription. However, it remains elusive how the order of the genome architecture related to its function. Here, we developed a single-cell Hi-C method and proposed TAD “degree of disorder” as a measure of genome organizational patterns, which is correlated with the chromatin epigenetic states, gene expression and co-regulation, and chromatin structure variability in individual cells. Upon Mycobacterium tuberculosis infection, NF-κB enters into the nucleus, binds to the target genome regions and initiates systematic chromatin conformation reorganization. Furthermore, we identified a remote NF-κB enriched enhancer promotes the expression of PD-L1 through chromatin loop, which could be a potential anti-tuberculosis and even anti-tumor therapeutic target. The integrated Hi-C, eQTL, and GWAS analysis depicted the atlas of the long-range target genes of tuberculosis susceptible loci. Among which SNP rs1873613 is located in the anchor of a dynamic chromatin loop with LRRK2, whose inhibitor AdoCbl could be an anti-tuberculosis drug candidate. Our study provides comprehensive resources for the 4D genome of immunocytes and sheds insights into the genome organization order and the coordinated gene transcription.

scholarly journals Associating disease-related genetic variants in intergenic regions to the genes they impact

2014 ◽  
Author(s):  
Geoff Macintyre ◽  
Antonio Jimeno Yepes ◽  
Cheng Soon Ong ◽  
Karin Verspoor
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Three Dimensional ◽  
Biomedical Literature ◽  
Dimensional Structure ◽  
Chromatin Conformation ◽  
Functional Interpretation ◽  
Chromatin Conformation Capture ◽  
Intergenic Regions ◽  
Small Test

We present a method to assist in interpretation of the functional impact of intergenic disease-associated SNPs that is not limited to search strategies proximal to the SNP. The method builds on two sources of external knowledge: the growing understanding of three-dimensional spatial relationships in the genome, and the substantial repository of information about relationships among genetic variants, genes, and diseases captured in the published biomedical literature. We integrate chromatin conformation capture data (HiC) with literature support to rank putative target genes of intergenic disease-associated SNPs. We demonstrate that this hybrid method outperforms a genomic distance baseline on a small test set of expression quantitative trait loci, as well as either method individually. In addition, we show the potential for this method to uncover relationships between intergenic SNPs and target genes across chromosomes. With more extensive chromatin conformation capture data becoming readily available, this method provides a way forward towards functional interpretation of SNPs in the context of the three dimensional structure of the genome in the nucleus.

scholarly journals Associating disease-related genetic variants in intergenic regions to the genes they impact

2014 ◽  
Author(s):  
Geoff Macintyre ◽  
Antonio Jimeno Yepes ◽  
Cheng Soon Ong ◽  
Karin Verspoor
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Three Dimensional ◽  
Biomedical Literature ◽  
Dimensional Structure ◽  
Chromatin Conformation ◽  
Functional Interpretation ◽  
Chromatin Conformation Capture ◽  
Intergenic Regions ◽  
Small Test

We present a method to assist in interpretation of the functional impact of intergenic disease-associated SNPs that is not limited to search strategies proximal to the SNP. The method builds on two sources of external knowledge: the growing understanding of three-dimensional spatial relationships in the genome, and the substantial repository of information about relationships among genetic variants, genes, and diseases captured in the published biomedical literature. We integrate chromatin conformation capture data (HiC) with literature support to rank putative target genes of intergenic disease-associated SNPs. We demonstrate that this hybrid method outperforms a genomic distance baseline on a small test set of expression quantitative trait loci, as well as either method individually. In addition, we show the potential for this method to uncover relationships between intergenic SNPs and target genes across chromosomes. With more extensive chromatin conformation capture data becoming readily available, this method provides a way forward towards functional interpretation of SNPs in the context of the three dimensional structure of the genome in the nucleus.

scholarly journals Regulation of gene transcription by Polycomb proteins

2015 ◽  
Vol 1 (11) ◽  
pp. e1500737 ◽  
Author(s):  
Sergi Aranda ◽  
Gloria Mas ◽  
Luciano Di Croce
Keyword(s):  
Gene Transcription ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Mechanisms Of Action ◽  
Polycomb Group ◽  
Chromatin Conformation ◽  
Polycomb Proteins ◽  
Positional Identity ◽  
And Function

The Polycomb group (PcG) of proteins defines a subset of factors that physically associate and function to maintain the positional identity of cells from the embryo to adult stages. PcG has long been considered a paradigmatic model for epigenetic maintenance of gene transcription programs. Despite intensive research efforts to unveil the molecular mechanisms of action of PcG proteins, several fundamental questions remain unresolved: How many different PcG complexes exist in mammalian cells? How are PcG complexes targeted to specific loci? How does PcG regulate transcription? In this review, we discuss the diversity of PcG complexes in mammalian cells, examine newly identified modes of recruitment to chromatin, and highlight the latest insights into the molecular mechanisms underlying the function of PcGs in transcription regulation and three-dimensional chromatin conformation.

scholarly journals Deeply hidden genome organization directly mediated by SATB1

2021 ◽  
Author(s):  
Yoshinori Kohwi ◽  
Mari Grange ◽  
Hunter W Richards ◽  
Ya-Chen Liang ◽  
Cheng-Ming Chuong ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Genome Architecture ◽  
Cell Type ◽  
Topologically Associated Domains ◽  
Chromatin Folding ◽  
Cell Type Specific ◽  
Cellular Phenotypes

Mammalian genomes are organized by multi-layered chromatin folding. Whether and how three-dimensional genome organization contributes to cell-type specific transcription remains unclear. Here we uncover genome architecture formed by specialized sequences, base-unpairing regions (BURs), bound to a nuclear architectural protein, SATB1. SATB1 regulates cell-type specific transcription that underlies changes in cellular phenotypes. We developed a modified ChIP-seq protocol that stringently purifies genomic DNA only with its directly-associated proteins and unmasked previously-hidden BURs as direct SATB1 targets genome-wide. These SATB1-bound BURs are mutually exclusive from CTCF binding sites, and SATB1 is dispensable for CTCF/cohesion-mediated topologically associated domains (TADs). Instead, BURs largely overlap with lamina associated domains (LADs), and the fraction of BURs tethered to the SATB1 protein network in the nuclear interior is cell type-dependent. Our results reveal TAD-independent chromatin folding mediated by BUR sequences, which serve as genome architecture landmarks targeted by SATB1, to regulate cell-type specific gene expression.

scholarly journals Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

2020 ◽  
Author(s):  
Celestia Fang ◽  
Zhenjia Wang ◽  
Cuijuan Han ◽  
Stephanie L. Safgren ◽  
Kathryn A. Helmin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transcription Factors ◽  
Genome Organization ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Dna Looping ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Comprehensive Survey

AbstractBackgroundThe three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, there is no hitherto a comprehensive survey of genome-wide CTCF binding patterns across different human cancers.ResultsTo dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions in patient samples, but not always with DNA methylation changes or sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events are induced by oncogenic transcription factors and exhibit enhancer activities. We validate these findings in T-cell acute lymphoblastic leukemia and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena.ConclusionsCancer-specific CTCF binding events are not always associated with DNA methylation changes or mutations, but can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

scholarly journals Plant 3-D Chromatin Organization: Important Insights from Chromosome Conformation Capture Analyses of the Last 10 Years

2021 ◽  
Author(s):  
Xinxin Zhang ◽  
Tianzuo Wang
Keyword(s):  
Genome Organization ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Three Dimensional ◽  
Chromatin Organization ◽  
Chromatin Conformation ◽  
D Genome ◽  
Chromatin Domains ◽  
Chromosome Conformation ◽  
Chromatin Conformation Capture

Abstract Over the past few decades, eukaryotic linear genomes and epigenomes have been widely and extensively studied for understanding gene expression regulation. More recently, the three-dimensional (3-D) chromatin organization was found to be important for determining genome functionality, finely tuning physiological processes for appropriate cellular responses. With the development of visualization techniques and chromatin conformation capture (3C)-based techniques, increasing evidence indicates that chromosomal architecture characteristics and chromatin domains with different epigenetic modification in the nucleus are correlated to transcriptional activities. Subsequent studies have further explored the intricate interplay between 3-D genome organization and the function of interacting regions. In this review, we summarize spatial distribution patterns of chromatin, including chromatin positioning, configurations and domains, with a particular focus on the effect of a unique form of interaction between a variety of factors that shapes the 3-D genome conformation in plants. We further discuss the methods, advantages and limitations of various chromatin conformation capture (3C)-based techniques, highlighting the applications of these technologies in plants to identify chromatin domains, and address their dynamic changes and functional implications in evolution, and adaptation to development and changing environmental conditions. Moreover, the future implications and emerging research directions of 3-D genome organization are discussed.

scholarly journals Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Celestia Fang ◽  
Zhenjia Wang ◽  
Cuijuan Han ◽  
Stephanie L. Safgren ◽  
Kathryn A. Helmin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Genome Organization ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Leukemia Cell ◽  
Dna Looping ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Human Cancers

Abstract Background The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. Results To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Conclusions Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.

scholarly journals MyoD is a structure organizer of 3D genome architecture in muscle cells

2020 ◽  
Author(s):  
Qian Chen ◽  
Fengling Chen ◽  
Ruiting Wang ◽  
Minglei Shi ◽  
Antony K. Chen ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Muscle Cells ◽  
Cell Types ◽  
Linear Molecule ◽  
Basic Question ◽  
Genome Architecture ◽  
Cell Type ◽  
3D Genome ◽  
A Genome

AbstractThe genome is not a linear molecule of DNA randomly folded in the nucleus, but exists as an organized, three-dimensional (3D) dynamic architecture. Intriguingly, it is now clear that each cell type has a unique and characteristic 3D genome organization that functions in determining cell identity during development. A currently challenging basic question is how cell-type specific 3D genome structures are established during development. Herein, we analyzed 3D genome structures in primary myoblasts and myocytes from MyoD knockout (MKO) and wild type (WT) mice and discovered that MyoD, a pioneer transcription factor (TF), can function as a “genome organizer” that specifies the proper 3D genome architecture unique to muscle cell development. Importantly, we genetically demonstrate that H3K27ac is insufficient for establishing MyoD-induced chromatin loops in muscle cells. The establishment of MyoD’s “architectural role” should have profound impacts on advancing understanding of other pioneer transcription factors in orchestrating lineage specific 3D genome organization during development in a potentially very large number of cell types in diverse organisms.

Methods for mapping three-dimensional genome architecture

Methods ◽  
2020 ◽  
Vol 170 ◽  
pp. 1-3
Author(s):  
Surabhi Chowdhary ◽  
Amoldeep S. Kainth ◽  
David S. Gross
Keyword(s):  
Three Dimensional ◽  
Genome Architecture

scholarly journals GAMIBHEAR: whole-genome haplotype reconstruction from Genome Architecture Mapping data

2021 ◽  
Author(s):  
Julia Markowski ◽  
Rieke Kempfer ◽  
Alexander Kukalev ◽  
Ibai Irastorza-Azcarate ◽  
Gesa Loof ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Embryonic Stem Cell Line ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Supplementary Information ◽  
Model Organisms ◽  
Genome Architecture ◽  
Chromatin Conformation ◽  
Haplotype Reconstruction ◽  
Allele Specific

Abstract Motivation Genome Architecture Mapping (GAM) was recently introduced as a digestion- and ligation-free method to detect chromatin conformation. Orthogonal to existing approaches based on chromatin conformation capture (3C), GAM’s ability to capture both inter- and intra-chromosomal contacts from low amounts of input data makes it particularly well suited for allele-specific analyses in a clinical setting. Allele-specific analyses are powerful tools to investigate the effects of genetic variants on many cellular phenotypes including chromatin conformation, but require the haplotypes of the individuals under study to be known a-priori. So far however, no algorithm exists for haplotype reconstruction and phasing of genetic variants from GAM data, hindering the allele-specific analysis of chromatin contact points in non-model organisms or individuals with unknown haplotypes. Results We present GAMIBHEAR, a tool for accurate haplotype reconstruction from GAM data. GAMIBHEAR aggregates allelic co-observation frequencies from GAM data and employs a GAM-specific probabilistic model of haplotype capture to optimise phasing accuracy. Using a hybrid mouse embryonic stem cell line with known haplotype structure as a benchmark dataset, we assess correctness and completeness of the reconstructed haplotypes, and demonstrate the power of GAMIBHEAR to infer accurate genome-wide haplotypes from GAM data. Availability GAMIBHEAR is available as an R package under the open source GPL-2 license at https://bitbucket.org/schwarzlab/gamibhear Maintainer [email protected] Supplementary information Supplementary information is available at Bioinformatics online.

Sign in / Sign up

Export Citation Format

Share Document