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 The future: genetics advances in MEN1 therapeutic approaches and management strategies

2017 ◽  
Vol 24 (10) ◽  
pp. T119-T134 ◽  
Author(s):  
Sunita K Agarwal
Keyword(s):  
Genetic Testing ◽  
Tumor Suppressor ◽  
Mouse Models ◽  
Target Genes ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Dimensional Structure

The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in theMEN1gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of theMEN1gene in MEN1-target tissues. Therefore,MEN1is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by theMEN1gene, menin, holds true in mouse models with germline heterozygousMen1loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of theMen1gene. The availability of genetic testing for mutations in theMEN1gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identifyMEN1germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.

scholarly journals Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants

Science ◽  
2020 ◽  
Vol 369 (6503) ◽  
pp. 561-565 ◽  
Author(s):  
Siwei Zhang ◽  
Hanwen Zhang ◽  
Yifan Zhou ◽  
Min Qiao ◽  
Siming Zhao ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Disease Risk ◽  
Induced Pluripotent Stem Cell ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Functional Interpretation ◽  
Neuropsychiatric Disease ◽  
Risk Variants ◽  
Allele Specific

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)–derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.

scholarly journals Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci

2019 ◽  
Vol 30 (3) ◽  
pp. 421-441 ◽  
Author(s):  
Karsten B. Sieber ◽  
Anna Batorsky ◽  
Kyle Siebenthall ◽  
Kelly L. Hudkins ◽  
Jeff D. Vierstra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kidney Disease ◽  
Genetic Variants ◽  
Target Genes ◽  
Mesangial Cells ◽  
Genome Wide Association ◽  
Chromatin Conformation ◽  
Genome Wide ◽  
Dna Elements ◽  
Regulatory Dna

BackgroundLinking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions containing regulatory DNA elements, such as promoters and enhancers. Although researchers have previously published DNA maps of these regulatory regions for kidney tubule cells and glomerular endothelial cells, maps for podocytes and mesangial cells have not been available.MethodsWe generated regulatory DNA maps (DNase-seq) and paired gene expression profiles (RNA-seq) from primary outgrowth cultures of human glomeruli that were composed mainly of podocytes and mesangial cells. We generated similar datasets from renal cortex cultures, to compare with those of the glomerular cultures. Because regulatory DNA elements can act on target genes across large genomic distances, we also generated a chromatin conformation map from freshly isolated human glomeruli.ResultsWe identified thousands of unique regulatory DNA elements, many located close to transcription factor genes, which the glomerular and cortex samples expressed at different levels. We found that genetic variants associated with kidney diseases (GWAS) and kidney expression quantitative trait loci were enriched in regulatory DNA regions. By combining GWAS, epigenomic, and chromatin conformation data, we functionally annotated 46 kidney disease genes.ConclusionsWe demonstrate a powerful approach to functionally connect kidney disease-/trait–associated loci to their target genes by leveraging unique regulatory DNA maps and integrated epigenomic and genetic analysis. This process can be applied to other kidney cell types and will enhance our understanding of genome regulation and its effects on gene expression in kidney disease.

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.

Sequence Analysis and Functional Interpretation of α-Amylase Receptor from Anopheles albimanus Using a Molecular Model

2013 ◽  
Vol 798-799 ◽  
pp. 1095-1098
Author(s):  
Shi Ping Shan ◽  
Dong Xia Du ◽  
De Yuan Zhang ◽  
Zhao Hui Guo
Keyword(s):  
Brush Border Membrane ◽  
Molecular Model ◽  
Membrane Vesicle ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Substrate Binding Pocket ◽  
Functional Interpretation ◽  
Three Dimensional Structure

Activated toxins interact with α-amylase receptor on the brush border membrane vesicle (BBMV) of the midgut epithelium, which activates intracellular oncotic pathways and leads to cell death. In order to decipher the mechanism of process how toxins interact with their receptors, it is essential to investigate their three-dimensional structure. The three-dimensional structure of α-amylase was constructed by homology modeling, based on crystal structure ofBacillus cereusoligo-1,6-glucosidase and the model was further evaluated using PROSA energy and ERRAT. The substrate binding pocket responsible for the interactions with toxins was predicted and analyzed, and the important role of binding of toxin to binding pocket on α-amylase was discussed in the aspect of Cry4Ba and Cry11Aa toxicity.

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 Plant and animal chromatin three-dimensional organization: similar structures but different functions

2020 ◽  
Vol 71 (17) ◽  
pp. 5119-5128 ◽  
Author(s):  
Pengfei Dong ◽  
Xiaoyu Tu ◽  
Zizheng Liang ◽  
Byung-Ho Kang ◽  
Silin Zhong
Keyword(s):  
Transcriptional Regulation ◽  
Genetic Information ◽  
Three Dimensional ◽  
Chromatin Conformation ◽  
Next Generation ◽  
Chromatin Conformation Capture ◽  
Hierarchical Levels ◽  
Chromatin Folding

Abstract Chromatin is the main carrier of genetic information and is non-randomly distributed within the nucleus. Next-generation sequence-based chromatin conformation capture technologies have enabled us to directly examine its three-dimensional organization at an unprecedented scale and resolution. In the best-studied mammalian models, chromatin folding can be broken down into three hierarchical levels, compartment, domains, and loops, which play important roles in transcriptional regulation. Although similar structures have now been identified in plants, they might not possess exactly the same functions as the mammalian ones. Here, we review recent Hi-C studies in plants, compare plant chromatin structures with their mammalian counterparts, and discuss the differences between plants with different genome sizes.

Differential GATA-1 Sensitivities of Target Loci.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1748-1748
Author(s):  
Kirby D. Johnson ◽  
Saumen Pal ◽  
Jeffrey A. Grass ◽  
Emery H. Bresnick
Keyword(s):  
Transcriptional Activation ◽  
Target Gene ◽  
Target Genes ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Erythroid Cell ◽  
Erythroid Precursor ◽  
Megakaryoblastic Leukemia ◽  
N Terminus

Abstract The transcription factor GATA-1 is a key regulator of red cell differentiation, activating numerous erythroid-specific genes while downregulating genes that permit proliferation of erythroid precursors. We have demonstrated that GATA-1 only occupies a limited number of the high affinity WGATAR motifs present within target gene loci, FOG-1 is required for GATA-1 to occupy a subset of chromatin sites, and GATA-1 occupancy often coincides with GATA-2 displacement or a “GATA switch”. Once bound, GATA-1 elicits changes in the histone modification patterns and the three dimensional structure of target gene loci via recruitment of cofactors such as FOG-1 and CBP. As detailed mechanistic studies have not been conducted with most GATA-1 target genes, it is unclear whether these genes are equally sensitive to GATA-1 or if they respond differently to the rising GATA-1 levels during erythropoiesis. Using GATA-1 fusions to the estrogen receptor ligand binding domain (ER-GATA-1) in the GATA-1-null erythroid precursor cell line, G1E, we analyzed the responses of endogenous GATA-1 target genes to varied levels of GATA-1 activity. We found that transcriptional activation of Tac-2 required higher concentrations of ER-GATA-1 than is required for other GATA-1 target genes. Previously, we showed that Tac-2, which encodes the neurokinin-B precursor protein preprotachykinin B, is regulated by GATA-1 in erythroid cell lines and is induced upon ex vivo differentiation of human CD34+ peripheral blood cells. Importantly, whereas regulation of many GATA-1 target genes is only partially disrupted by removal of the N-terminal 193 amino acids from ER-GATA-1 (ER-GATA-1 ΔN), Tac-2 expression was very sensitive to this truncation. Whereas NK-B signals through G-protein-coupled receptors to modulate neuronal function, its functions beyond the nervous system are poorly understood. Although erythroid cells do not express NK-B receptors, the receptors, but not NK-B, are expressed in certain endothelial cell subtypes, and elevated levels of NK-B are implicated in the pregnancy-associated disorder pre-eclampsia. Tac-2 represents the first GATA-1 target gene that critically requires the N-terminus. Studies are underway to elucidate mechanisms underlying the exquisite sensitivity of Tac-2 to deletion of the GATA-1 N-terminus, the relationship between Tac-2 deregulation and GATA-1 N-terminal deletions in megakaryoblastic leukemia, and the function of erythroid cell-derived NK-B.

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

Sign in / Sign up

Export Citation Format

Share Document