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Cell Dec 2017There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to...
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
Topics: Animals; CCCTC-Binding Factor; Embryonic Stem Cells; Enhancer Elements, Genetic; Humans; Mice; Promoter Regions, Genetic; YY1 Transcription Factor
PubMed: 29224777
DOI: 10.1016/j.cell.2017.11.008 -
Nucleic Acids Research Jan 2019COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic...
COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC's deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.
Topics: Databases, Nucleic Acid; Genes; Humans; Mutation; Neoplasms; Protein Conformation
PubMed: 30371878
DOI: 10.1093/nar/gky1015 -
Cell Feb 2021Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. However, 3D genome...
Both transcription and three-dimensional (3D) architecture 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 generated a transcriptome (3,517 cells) and 3D genome (3,646 cells) atlas of the developing mouse cortex and hippocampus by using our high-resolution multiple annealing and looping-based amplification cycles for digital transcriptomics (MALBAC-DT) and diploid chromatin conformation capture (Dip-C) methods and developing multi-omic analysis pipelines. In adults, 3D genome "structure types" delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first post-natal month. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. These findings uncover an unknown dimension of neurodevelopment.
Topics: Alleles; Animals; Animals, Newborn; Brain; Cell Lineage; Chromatin; Gene Expression Regulation, Developmental; Gene Ontology; Gene Regulatory Networks; Genetic Loci; Genome; Genomic Imprinting; Mice; Multigene Family; Neuroglia; Neurons; Sensation; Transcription, Genetic; Transcriptome; Visual Cortex
PubMed: 33484631
DOI: 10.1016/j.cell.2020.12.032 -
Nature Jan 2022Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections. The bacterial natural product colistin is considered...
Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin. Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens. In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.
Topics: Acinetobacter baumannii; Animals; Anti-Bacterial Agents; Biosynthetic Pathways; Colistin; Drug Resistance, Bacterial; Ethanolamines; Genes, Bacterial; Genome, Bacterial; Gram-Negative Bacteria; Mice; Microbial Sensitivity Tests; Multigene Family; Neutropenia; Plasmids; Transferases (Other Substituted Phosphate Groups)
PubMed: 34987225
DOI: 10.1038/s41586-021-04264-x -
Genomics Mar 2021Here, 38 wheat PYL genes (TaPYLs) belonging to 13 homoeologous groups were identified using the genome-search method, with 26 and 12 PYL genes identified in Triticum...
Here, 38 wheat PYL genes (TaPYLs) belonging to 13 homoeologous groups were identified using the genome-search method, with 26 and 12 PYL genes identified in Triticum dicoccoides and Aegilops tauschii, respectively. Phylogenetic relationship, conserved domain and molecular evolution analysis revealed that PYL genes showed highly conservative between wheat and theprogenitors. Interaction network and miRNA target prediction found that TaPYLs could interact with the important components of ABA signaling pathway and Tae-miR966b-3p might be a hub regulator mediating wheat ABA signal network. Furthermore, the tissue-specific and stress-responsive TaPYLs were detected through RNA-seq analysis. Expressions of 10 TaPYLs were validated by QPCR analysis and the homoeologous genes showed significantly differential expression, suggesting subfunctionalization of them has occurred. Finally, 3D structures of the TaPYL proteins were predicted by homology modeling. This study lays the foundation for further functional study of PYL genes for development and stress tolerance improvement in wheat and beyond.
Topics: Conserved Sequence; Evolution, Molecular; Exons; Introns; Multigene Family; Plant Proteins; Protein Domains; Triticum
PubMed: 33321205
DOI: 10.1016/j.ygeno.2020.12.017 -
Trends in Genetics : TIG Jan 2022Gene duplication is a prevalent phenomenon across the tree of life. The processes that lead to the retention of duplicated genes are not well understood. Functional... (Review)
Review
Gene duplication is a prevalent phenomenon across the tree of life. The processes that lead to the retention of duplicated genes are not well understood. Functional genomics approaches in model organisms, such as yeast, provide useful tools to test the mechanisms underlying retention with functional redundancy and divergence of duplicated genes, including fates associated with neofunctionalization, subfunctionalization, back-up compensation, and dosage amplification. Duplicated genes may also be retained as a consequence of structural and functional entanglement. Advances in human gene editing have enabled the interrogation of duplicated genes in the human genome, providing new tools to evaluate the relative contributions of each of these factors to duplicate gene retention and the evolution of genome structure.
Topics: Evolution, Molecular; Gene Duplication; Genes, Duplicate; Humans; Saccharomyces cerevisiae
PubMed: 34294428
DOI: 10.1016/j.tig.2021.06.016 -
Plant Communications Mar 2022Plants produce a remarkable diversity of structurally and functionally diverse natural chemicals that serve as adaptive compounds throughout their life cycles. However,... (Review)
Review
Plants produce a remarkable diversity of structurally and functionally diverse natural chemicals that serve as adaptive compounds throughout their life cycles. However, unlocking this metabolic diversity is significantly impeded by the size, complexity, and abundant repetitive elements of typical plant genomes. As genome sequencing becomes routine, we anticipate that links between metabolic diversity and genetic variation will be strengthened. In addition, an ever-increasing number of plant genomes have revealed that biosynthetic gene clusters are not only a hallmark of microbes and fungi; gene clusters for various classes of compounds have also been found in plants, and many are associated with important agronomic traits. We present recent examples of plant metabolic diversification that have been discovered through the exploration and exploitation of various genomic and pan-genomic data. We also draw attention to the fundamental genomic and pan-genomic basis of plant chemodiversity and discuss challenges and future perspectives for investigating metabolic diversity in the coming pan-genomics era.
Topics: Genome, Plant; Genomics; Multigene Family; Plants; Repetitive Sequences, Nucleic Acid
PubMed: 35529944
DOI: 10.1016/j.xplc.2022.100300 -
The Plant Journal : For Cell and... Feb 2018Pseudogenes have a reputation of being 'evolutionary relics' or 'junk DNA'. While they are well characterized in mammals, studies in more complex plant genomes have so...
Pseudogenes have a reputation of being 'evolutionary relics' or 'junk DNA'. While they are well characterized in mammals, studies in more complex plant genomes have so far been hampered by the absence of reference genome sequences. Barley is one of the economically most important cereals and has a genome size of 5.1 Gb. With the first high-quality genome reference assembly available for a Triticeae crop, we conducted a whole-genome assessment of pseudogenes on the barley genome. We identified, characterized and classified 89 440 gene fragments and pseudogenes scattered along the chromosomes, with occasional hotspots and higher densities at the chromosome ends. Full-length pseudogenes (11 015) have preferentially retained their exon-intron structure. Retrotransposition of processed mRNAs only plays a marginal role in their creation. However, the distribution of retroposed pseudogenes reflects the Rabl configuration of barley chromosomes and thus hints at founding mechanisms. While parent genes related to the defense-response were found to be under-represented in cultivated barley, we detected several defense-related pseudogenes in wild barley accessions. The percentage of transcriptionally active pseudogenes is 7.2%, and these may potentially adopt new regulatory roles.The barley genome is rich in pseudogenes and small gene fragments mainly located towards chromosome tips or as tandemly repeated units. Our results indicate non-random duplication and pseudogenization preferences and improve our understanding of the dynamics of gene birth and death in large plant genomes and the mechanisms that lead to evolutionary innovations.
Topics: Chromosome Mapping; Chromosomes, Plant; Gene Duplication; Genes, Plant; Hordeum; Multigene Family; Pseudogenes; Selection, Genetic; Synteny
PubMed: 29205595
DOI: 10.1111/tpj.13794 -
RNA Biology Jan 2023The genomic arrangement of most picornavirus of the family shares a similar monocistronic genomic pattern and a defining organizational feature. A defining feature of... (Review)
Review
The genomic arrangement of most picornavirus of the family shares a similar monocistronic genomic pattern and a defining organizational feature. A defining feature of picornavirus is the presence of evolutionarily conserved and highly-structured RNA elements in untranslated regions (UTRs) at the genome' 5'and 3' ends, essential for viral replication and translation. Given the diversity and complexity of RNA structure and the limitations of molecular biology techniques, the functional characterization and biological significance of UTRs remain to be fully elucidated, especially for 5' UTR. Here, we summarize the current knowledge of the 5' UTR of picornavirus. This review focuses on the structural characterization and the biological function of the RNA secondary and tertiary structures in the 5' UTR of picornavirus. Understanding the role of the 5' UTR of picornavirus can provide a deep insight into the viral replication cycle and pathogenic mechanisms.
Topics: 5' Untranslated Regions; Ribosomes; Nucleic Acid Conformation; Picornaviridae; RNA, Viral; 3' Untranslated Regions
PubMed: 37534989
DOI: 10.1080/15476286.2023.2240992 -
Nucleic Acids Research Jul 2015PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both...
PathWhiz (http://smpdb.ca/pathwhiz) is a web server designed to create colourful, visually pleasing and biologically accurate pathway diagrams that are both machine-readable and interactive. As a web server, PathWhiz is accessible from almost any place and compatible with essentially any operating system. It also houses a public library of pathways and pathway components that can be easily viewed and expanded upon by its users. PathWhiz allows users to readily generate biologically complex pathways by using a specially designed drawing palette to quickly render metabolites (including automated structure generation), proteins (including quaternary structures, covalent modifications and cofactors), nucleic acids, membranes, subcellular structures, cells, tissues and organs. Both small-molecule and protein/gene pathways can be constructed by combining multiple pathway processes such as reactions, interactions, binding events and transport activities. PathWhiz's pathway replication and propagation functions allow for existing pathways to be used to create new pathways or for existing pathways to be automatically propagated across species. PathWhiz pathways can be saved in BioPAX, SBGN-ML and SBML data exchange formats, as well as PNG, PWML, HTML image map or SVG images that can be viewed offline or explored using PathWhiz's interactive viewer. PathWhiz has been used to generate over 700 pathway diagrams for a number of popular databases including HMDB, DrugBank and SMPDB.
Topics: Animals; Computer Graphics; Disease; Genes; Humans; Internet; Metabolic Networks and Pathways; Mice; Protein Interaction Mapping; Signal Transduction; Software
PubMed: 25934797
DOI: 10.1093/nar/gkv399