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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the transcript life cycle [Nanostring]

ABSTRACT: Series of regulatory mechanisms control eukaryotic mRNAs, from their production on chromatin to their eventual degradation. Dissecting these pathways requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and the cytoplasm. All rates displayed substantial variability genome-wide, and transcripts from genes with related functions flowed across subcellular compartments with similar kinetics. For some genes, most transcripts were rapidly degraded within the nucleus, while the remaining molecules were exported and persisted with stable lifespans. With compartment-specific measurements of poly(A) tail lengths, we found that relationships between tail length and stability differ across the cell. The targets of RNA binding proteins experience distinct RNA flow kinetics, and we found that two, DDX3X and PABPC4, act by controlling the nuclear export of their targets. Finally, we developed a machine learning model to propose additional molecular features that underlie the diverse life cycle of mammalian mRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207925 | GEO | 2024/07/03

REPOSITORIES: GEO

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the transcript life cycle

Project description:Series of regulatory mechanisms control eukaryotic mRNAs, from their production on chromatin to their eventual degradation. Dissecting these pathways requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and the cytoplasm. All rates displayed substantial variability genome-wide, and transcripts from genes with related functions flowed across subcellular compartments with similar kinetics. For some genes, most transcripts were rapidly degraded within the nucleus, while the remaining molecules were exported and persisted with stable lifespans. With compartment-specific measurements of poly(A) tail lengths, we found that relationships between tail length and stability differ across the cell. The targets of RNA binding proteins experience distinct RNA flow kinetics, and we found that two, DDX3X and PABPC4, act by controlling the nuclear export of their targets. Finally, we developed a machine learning model to propose additional molecular features that underlie the diverse life cycle of mammalian mRNAs.

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the transcript life cycle [RNA-seq]

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle [RNAseq]

Project description:Dissecting the myriad regulatory mechanisms controlling eukaryotic transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered roles for DDX3X and PABPC4 in nuclear export. For hundreds of genes, most transcripts were degraded within the nucleus, while the remaining molecules were exported and persisted with stable lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, a machine learning model identified additional molecular features that underlie the diverse life cycles of mammalian mRNAs.

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle.

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle

Project description:Dissecting the regulatory mechanisms controlling mammalian transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm in human and mouse cells. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA-binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered a link between DDX3X and nuclear export. For hundreds of RNA metabolism genes, most transcripts with retained introns were degraded by the nuclear exosome, while the remaining molecules were exported with stable cytoplasmic lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, machine learning identified molecular features that predicted the diverse life cycles of mRNAs.

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Characterisation of the temporal hepatic transcriptome at subcellular level

Project description:In eukaryotes, RNA is synthesized in the nucleus, spliced, and exported to the cytoplasm where it is translated and finally degraded. Any of these steps could be subject to temporal regulation during the circadian cycle, generating daily fluctuations of RNA accumulation and impacting the distribution of transcripts in different subcellular compartments. Here, we performed a comprehensive analysis of nuclear and cytoplasmic, polyA and total, transcriptomes of mouse livers sampled along the daily cycle. These data provide a genome-wide temporal inventory of RNA subcellular enrichments, and revealed specific signatures of splicing, nuclear export and cytoplasmic mRNA stability related to transcript and gene lengths. Combined with a mathematical model describing rhythmic RNA profiles , we could test the rhyhtmicity of export rates and cytoplasmic degradation rates of ~1400 genes. While nuclear export times are usually much shorter than cytoplasmic half-lives, we found that that nuclear export contributes to the modulation and generation of rhythmic profiles of ~10% of the cycling nuclear mRNAs. This study provides an estimation of the nuclear and cytoplasmic life times in the liver and contributes to a better understanding of the dynamic regulation of the transcriptome during the feeding-fasting cycle.

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Project description:In this work, we quantified mRNA flow rates between subcellular compartments in mouse embryonic stem cells. Combining metabolic RNA labeling, biochemical cell fractionation and RNA sequencing with mathematical modeling we were able to determine the kinetic rates of nuclear pre-, nuclear mature, cytosolic and membrane mRNA derived from more than 9000 protein-coding genes. For more than 5000 genes, we additionally estimated the transcript elongation rate. For most of the transcripts, mature nuclear half-lives are the longest, suggesting nuclear retention to be the rate-limiting step in the mRNA life cycle. Genes encoding transcription factors and immediate early genes possess fast kinetic rates, specifically a short nuclear half-life. Differentially localized mRNAs exhibit distinct combinations of rate constants, suggesting modular control within subcellular compartments. We show that membrane stability is high for membrane-localized mRNA and that cytosolic stability is high for cytosol-localized mRNA. Genes encoding target signals, such as signal peptides or transmembrane domains, have low cytosolic and high membrane half-lives with only slight differences between target signals. Nuclear-encoded mitochondrial proteins show long nuclear mature half-lives and otherwise similar features of cytoplasmic kinetics that do not resemble co-translational targeting to the mitochondria.

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Quantification of subcellular mRNA kinetics in mouse embryonic stem cells

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Ultra short and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution

Project description:RNA synthesis and decay rates determine the steady-state levels of cellular RNAs. Metabolic tagging of newly transcribed RNA by 4-thiouridine (4sU) can reveal the relative contributions of RNA synthesis and decay rates. The kinetics of RNA processing, however, so far remained unresolved. Here, we show that ultra-short 4sU-tagging not only provides snap-shot pictures of eukaryotic gene expression but, when combined with progressive 4sU-tagging and RNA-seq, reveals global RNA processing kinetics at nucleotide resolution. Using this method, we identified classes of rapidly and slowly spliced/degraded introns. Interestingly, each class of splicing kinetics was characterized by a distinct association with intron length, gene length and splice site strength. For a large group of introns, we also observed long lasting retention in the primary transcript, but efficient secondary splicing or degradation at later time points. Finally, we show that processing of most, but not all small nucleolar (sno)RNA-containing introns is remarkably inefficient with the majority of introns being spliced and degraded rather than processed into mature snoRNAs. In summary, our study yields unparalleled insights into the kinetics of RNA processing and provides the tools to study molecular mechanisms of RNA processing and their contribution to the regulation of gene expression. 4sU-tagging was performed in human DG75 B-cells by adding 500 uM 4sU to cell culture medium for 5, 10, 15, 20 or 60 min. Following isolation of total cellular RNA, this was separated into nascent and untagged, pre-existing RNA. Nascent RNA as well as total and untagged RNA from 60 min 4sU-tagging were subjected to SOLiD sequencing (SOLiD II) obtaining 35 nt reads.

2012-04-25 | E-GEOD-31653 | biostudies-arrayexpress

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