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International Journal of Molecular... Feb 2023As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5' untranslated region (5'UTR), which itself contains many... (Review)
Review
As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5' untranslated region (5'UTR), which itself contains many regulatory elements such as upstream ORFs (uORFs), internal ribosome entry sites (IRESs), microRNA binding sites, and structural components involved in the regulation of mRNA stability, pre-mRNA splicing, and translation initiation. Activation of the alternative, more upstream transcription start site leads to an extension of 5'UTR. One of the consequences of 5'UTRs extension may be head-to-head gene overlap. This review describes elements in 5'UTR of protein-coding transcripts and the functional significance of protein-coding genes 5' overlap with implications for transcription, translation, and disease.
Topics: 5' Untranslated Regions; Protein Biosynthesis; RNA, Messenger; Gene Expression Regulation; Regulatory Sequences, Nucleic Acid
PubMed: 36769304
DOI: 10.3390/ijms24032976 -
Nature Dec 2022Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D)...
Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer. However, only a small minority of SVs are associated with altered gene expression, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analysing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT and CCND1. By using CRISPR-Cas9 genome engineering to generate de novo SVs, we show that oncogene activity can be predicted by using 'activity-by-contact' models that consider partner region chromatin contacts and enhancer activity. However, activity-by-contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that SVs that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of SVs on oncogene activation.
Topics: Humans; Chromatin; Gene Rearrangement; Genomic Structural Variation; Neoplasms; Oncogenes; Oncogene Proteins; Chromosomes, Human; Cell Line, Tumor; Enhancer Elements, Genetic; Models, Genetic
PubMed: 36477537
DOI: 10.1038/s41586-022-05504-4 -
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 -
BMC Genomics Jun 2022The R2R3-MYB transcription factor is one of the largest gene families in plants and involved in the regulation of plant development, hormone signal transduction, biotic...
BACKGROUND
The R2R3-MYB transcription factor is one of the largest gene families in plants and involved in the regulation of plant development, hormone signal transduction, biotic and abiotic stresses. Tobacco is one of the most important model plants. Therefore, it will be of great significance to investigate the R2R3-MYB gene family and their expression patterns under abiotic stress and senescence in tobacco.
RESULTS
A total of 174 R2R3-MYB genes were identified from tobacco (Nicotiana tabacum L.) genome and were divided into 24 subgroups based on phylogenetic analysis. Gene structure (exon/intron) and protein motifs were especially conserved among the NtR2R3-MYB genes, especially members within the same subgroup. The NtR2R3-MYB genes were distributed on 24 tobacco chromosomes. Analysis of gene duplication events obtained 3 pairs of tandem duplication genes and 62 pairs of segmental duplication genes, suggesting that segmental duplications is the major pattern for R2R3-MYB gene family expansion in tobacco. Cis-regulatory elements of the NtR2R3-MYB promoters were involved in cellular development, phytohormones, environmental stress and photoresponsive. Expression profile analysis showed that NtR2R3-MYB genes were widely expressed in different maturity tobacco leaves, and however, the expression patterns of different members appeared to be diverse. The qRT-PCR analysis of 15 NtR2R3-MYBs confirmed their differential expression under different abiotic stresses (cold, salt and drought), and notably, NtMYB46 was significantly up-regulated under three treatments.
CONCLUSIONS
In summary, a genome-wide identification, evolutionary and expression analysis of R2R3-MYB gene family in tobacco were conducted. Our results provided a solid foundation for further biological functional study of NtR2R3-MYB genes in tobacco.
Topics: Amino Acid Sequence; Gene Expression Regulation, Plant; Genes, myb; Multigene Family; Phylogeny; Plant Proteins; Nicotiana
PubMed: 35681121
DOI: 10.1186/s12864-022-08658-7 -
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 -
Genome Research Mar 2023Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely...
Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here we generated high-quality genome assemblies for 15 individuals from genetically diverse sheep breeds using Pacific Biosciences (PacBio) high-fidelity sequencing, discovering 130.3 Mb nonreference sequences, from which 588 genes were annotated. A total of 149,158 biallelic insertions/deletions, 6531 divergent alleles, and 14,707 multiallelic variations with precise breakpoints were discovered. The SV spectrum is characterized by an excess of derived insertions compared to deletions (94,422 vs. 33,571), suggesting recent active LINE expansions in sheep. Nearly half of the SVs display low to moderate linkage disequilibrium with surrounding single-nucleotide polymorphisms (SNPs) and most SVs cannot be tagged by SNP probes from the widely used ovine 50K SNP chip. We identified 865 population-stratified SVs including 122 SVs possibly derived in the domestication process among 690 individuals from sheep breeds worldwide. A novel 168-bp insertion in the 5' untranslated region (5' UTR) of is found at high frequency in long-tailed sheep. Further genome-wide association study and gene expression analyses suggest that this mutation is causative for the long-tail trait. In summary, we have developed a panel of high-quality de novo assemblies and present a catalog of structural variations in sheep. Our data capture abundant candidate functional variations that were previously unexplored and provide a fundamental resource for understanding trait biology in sheep.
Topics: Animals; Sheep; Genome-Wide Association Study; Tail; 5' Untranslated Regions; Alleles; Phenotype
PubMed: 37310928
DOI: 10.1101/gr.277372.122 -
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 -
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