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Trends in Genetics : TIG Sep 2023Transcription of eukaryotic genes by RNA polymerase II (Pol II) yields RNA precursors containing introns that must be spliced out and the flanking exons ligated... (Review)
Review
Transcription of eukaryotic genes by RNA polymerase II (Pol II) yields RNA precursors containing introns that must be spliced out and the flanking exons ligated together. Splicing is catalyzed by a dynamic ribonucleoprotein complex called the spliceosome. Recent evidence has shown that a large fraction of splicing occurs cotranscriptionally as the RNA chain is extruded from Pol II at speeds of up to 5 kb/minute. Splicing is more efficient when it is tethered to the transcription elongation complex, and this linkage permits functional coupling of splicing with transcription. We discuss recent progress that has uncovered a network of connections that link splicing to transcript elongation and other cotranscriptional RNA processing events.
Topics: RNA Precursors; Transcription, Genetic; RNA Splicing; Spliceosomes; Introns
PubMed: 37236814
DOI: 10.1016/j.tig.2023.04.008 -
Molecular Cell Aug 2023The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and... (Review)
Review
The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to (1) delineate dynamics of nuclear architecture at different timescales, from minutes to weeks as cells differentiate, in populations and in single cells, (2) characterize cis-determinants and trans-modulators of genome organization, (3) test functional consequences of changes in cis- and trans-regulators, and (4) develop predictive models of genome structure and function.
Topics: Genome; Cell Nucleus; Chromatin
PubMed: 37419111
DOI: 10.1016/j.molcel.2023.06.018 -
Cell Death & Disease Jul 2023The THO complex (THOC) is ubiquitously involved in RNA modification and various THOC proteins have been reported to regulate tumor development. However, the role of...
The THO complex (THOC) is ubiquitously involved in RNA modification and various THOC proteins have been reported to regulate tumor development. However, the role of THOC3 in lung cancer remains unknown. In this study, we identified that THOC3 was highly expressed in lung squamous cell carcinoma (LUSC) and negatively associated with prognosis. THOC3 knockdown inhibited LUSC cell growth, migration, and glycolysis. THOC3 expression was regulated by TRiC proteins, such as CCT8 and CCT6A, which supported protein folding. Furthermore, THOC3 could form a complex with YBX1 to promote PFKFB4 transcription. THOC3 was responsible for exporting PFKFB4 mRNA to the cytoplasm, while YBX1 ensured the stability of PFKFB4 mRNA by recognizing m5C sites in its 3'UTR. Downregulation of PFKFB4 suppressed the biological activities of LUSC. Collectively, these findings suggest that THOC3, folded by CCT proteins can collaborate with YBX1 to maintain PFKFB4 expression and facilitate LUSC development. Therefore, THOC3 could be considered as a novel promising therapeutic target for LUSC.
Topics: Humans; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Chaperonin Containing TCP-1; Gene Expression Regulation, Neoplastic; Lung; Lung Neoplasms; Phosphofructokinase-2; Phosphoric Monoester Hydrolases; RNA, Messenger; Y-Box-Binding Protein 1; RNA-Binding Proteins
PubMed: 37500615
DOI: 10.1038/s41419-023-06008-3 -
Chromosoma Sep 2023Chemical modifications of nucleotides expand the complexity and functional properties of genomes and transcriptomes. A handful of modifications in DNA bases are part of... (Review)
Review
Chemical modifications of nucleotides expand the complexity and functional properties of genomes and transcriptomes. A handful of modifications in DNA bases are part of the epigenome, wherein DNA methylation regulates chromatin structure, transcription, and co-transcriptional RNA processing. In contrast, more than 150 chemical modifications of RNA constitute the epitranscriptome. Ribonucleoside modifications comprise a diverse repertoire of chemical groups, including methylation, acetylation, deamination, isomerization, and oxidation. Such RNA modifications regulate all steps of RNA metabolism, including folding, processing, stability, transport, translation, and RNA's intermolecular interactions. Initially thought to influence all aspects of the post-transcriptional regulation of gene expression exclusively, recent findings uncovered a crosstalk between the epitranscriptome and the epigenome. In other words, RNA modifications feedback to the epigenome to transcriptionally regulate gene expression. The epitranscriptome achieves this feat by directly or indirectly affecting chromatin structure and nuclear organization. This review highlights how chemical modifications in chromatin-associated RNAs (caRNAs) and messenger RNAs (mRNAs) encoding factors involved in transcription, chromatin structure, histone modifications, and nuclear organization affect gene expression transcriptionally.
Topics: Epigenome; Chromatin; Gene Expression Regulation; RNA; DNA Methylation; RNA, Messenger; RNA Processing, Post-Transcriptional
PubMed: 37138119
DOI: 10.1007/s00412-023-00794-7 -
Journal of Bioinformatics and... Aug 2023Most of the functional RNA elements located within large transcripts are local. Local folding therefore serves a practically useful approximation to global structure...
Most of the functional RNA elements located within large transcripts are local. Local folding therefore serves a practically useful approximation to global structure prediction. Due to the sensitivity of RNA secondary structure prediction to the exact definition of sequence ends, accuracy can be increased by averaging local structure predictions over multiple, overlapping sequence windows. These averages can be computed efficiently by dynamic programming. Here we revisit the local folding problem, present a concise mathematical formalization that generalizes previous approaches and show that correct Boltzmann samples can be obtained by local stochastic backtracing in McCaskill's algorithms but not from local folding recursions. Corresponding new features are implemented in the ViennaRNA package to improve the support of local folding. Applications include the computation of maximum expected accuracy structures from RNAplfold data and a mutual information measure to quantify the sensitivity of individual sequence positions.
Topics: RNA Folding; Nucleic Acid Conformation; RNA; Algorithms; RNA, Untranslated
PubMed: 37522173
DOI: 10.1142/S0219720023500166 -
DNA and Cell Biology Oct 2023Heat shock protein 90 (HSP90) family is a class of proteins known as molecular chaperones that promote client protein folding and translocation in unstressed cells and... (Review)
Review
Heat shock protein 90 (HSP90) family is a class of proteins known as molecular chaperones that promote client protein folding and translocation in unstressed cells and regulate cellular homeostasis in the stress response. Noncoding RNAs (ncRNAs) are defined as RNAs that do not encode proteins. Previous studies have shown that ncRNAs are key regulators of multiple fundamental cellular processes, such as development, differentiation, proliferation, transcription, post-transcriptional modifications, apoptosis, and cell metabolism. It is known that ncRNAs do not act alone but function via the interactions with other molecules, including co-chaperones, RNAs, DNAs, and so on. As a kind of molecular chaperone, HSP90 is also involved in many biological procedures of ncRNAs. In this review, we systematically analyze the impact of HSP90 on various kinds of ncRNAs, including their synthesis and function, and how ncRNAs influence HSP90 directly and indirectly.
Topics: Humans; HSP90 Heat-Shock Proteins; Molecular Chaperones; RNA, Untranslated
PubMed: 37638805
DOI: 10.1089/dna.2023.0172 -
Journal of Molecular Biology Dec 2023The mRNA coding sequence defines not only the amino acid sequence of the protein, but also the speed at which the ribosomes move along the mRNA while making the protein.... (Review)
Review
The mRNA coding sequence defines not only the amino acid sequence of the protein, but also the speed at which the ribosomes move along the mRNA while making the protein. The non-uniform local kinetics - denoted as translational rhythm - is similar among mRNAs coding for related protein folds. Deviations from this conserved rhythm can result in protein misfolding. In this review we summarize the experimental evidence demonstrating how local translation rates affect cotranslational protein folding, with the focus on the synonymous codons and patches of charged residues in the nascent peptide as best-studied examples. Alterations in nascent protein conformations due to disturbed translational rhythm can persist off the ribosome, as demonstrated by the effects of synonymous codon variants of several disease-related proteins. Charged amino acid patches in nascent chains also modulate translation and cotranslational protein folding, and can abrogate translation when placed at the N-terminus of the nascent peptide. During cotranslational folding, incomplete nascent chains navigate through a unique conformational landscape in which earlier intermediate states become inaccessible as the nascent peptide grows. Precisely tuned local translation rates, as well as interactions with the ribosome, guide the folding pathway towards the native structure, whereas deviations from the natural translation rhythm may favor pathways leading to trapped misfolded states. Deciphering the 'folding code' of the mRNA will contribute to understanding the diseases caused by protein misfolding and to rational protein design.
PubMed: 38065274
DOI: 10.1016/j.jmb.2023.168384 -
Current Opinion in Structural Biology Oct 2023Chromosomes in all domains of life are well-defined structural entities with complex hierarchical organization. The regulation of this hierarchical organization and its... (Review)
Review
Chromosomes in all domains of life are well-defined structural entities with complex hierarchical organization. The regulation of this hierarchical organization and its functional interplay with gene expression or other chromosome metabolic processes such as repair, replication, or segregation is actively investigated in a variety of species, including prokaryotes. Bacterial chromosomes are typically gene-dense with few non-coding sequences and are organized into the nucleoid, a membrane-less compartment composed of DNA, RNA, and proteins (nucleoid-associated proteins or NAPs). The continuous improvement of imaging and genomic methods has put the organization of these Mb-long molecules at reach, allowing to disambiguate some of their highly dynamic properties and intertwined structural features. Here we review and discuss some of the recent advances in the field of bacterial chromosome organization.
Topics: Genome, Bacterial; Genomics; Prokaryotic Cells; RNA
PubMed: 37604045
DOI: 10.1016/j.sbi.2023.102679 -
Frontiers in Genetics 2024
PubMed: 38456016
DOI: 10.3389/fgene.2024.1382435 -
Nature Aug 2023The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions. Although the molecular rules governing...
The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.
Topics: Humans; Chromatin; Chromosome Positioning; Chromosomes, Human; DNA; Genome, Human; Glycogen Synthase Kinases; High-Throughput Screening Assays; Interphase; Reproducibility of Results; RNA; Signal Transduction; Single-Cell Analysis; Cohesins
PubMed: 37438531
DOI: 10.1038/s41586-023-06340-w