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Extension of mRNA poly(A) tails and 3′UTRs during neuronal differentiation exhibits variable association with post-transcriptional dynamics

ABSTRACT: Differentiation of neural progenitor cells into mature neuronal phenotypes relies on extensive temporospatial coordination of mRNA expression to support the development of functional brain circuitry. Cleavage and polyadenylation of mRNA has tremendous regulatory capacity through the alteration of mRNA stability and modulation of microRNA (miRNA) function, however the extent of utilization in neuronal development is currently unclear. Here, we employed poly(A) tail sequencing, mRNA sequencing, ribosome profiling and small RNA sequencing to explore the functional relationship between mRNA abundance, translation, poly(A) tail length, alternative polyadenylation (APA) and miRNA expression in an in vitro model of neuronal differentiation. Differential analysis revealed a strong bias towards poly(A) tail and 3´UTR lengthening during differentiation, both of which were associated with changes in mRNA abundance but not translation. Globally, changes in miRNA expression were predominantly associated with mRNA abundance and translation, however several miRNA-mRNA pairings with potential to regulate poly(A) tail length were identified. Furthermore, 3´UTR lengthening was observed to significantly increase the inclusion of non-conserved miRNA binding sites, potentially enhancing the regulatory capacity of these molecules in mature neuronal cells. Together, our findings suggest poly(A) tail length and APA function as part of a rich post-transcriptional regulatory matrix during neuronal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155432 | GEO | 2023/06/09

REPOSITORIES: GEO

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mRNA Poly(A)-tail Changes Specified by Deadenylation Broadly Reshape Translation in Drosophila Oocytes and Early Embryos

Project description:Because maturing oocytes and early embryos lack transcription, posttranscriptional regulatory processes must control their development. To better understand this control, we profiled translational efficiencies and poly(A)-tail lengths throughout Drosophila oocyte maturation and early embryonic development. The correspondence between translational-efficiency changes and tail-length changes indicated that tail-length changes broadly reshape translational activity until gastrulation, when this coupling disappears. Relative changes were largely retained in the absence of poly(A)-tail lengthening, which indicated that selective poly(A)-tail shortening primarily specifies the changes. Many translational changes depended on PAN GU and Smaug, and both acted primarily through tail-length changes. Our results also revealed tail-lengthâindependent mechanisms of translational control that repressed translation regardless of tail-length changes during oocyte maturation, maintained translation despite tail-length shortening during oocyte maturation, and prevented detectable translation of bicoid and several other mRNAs before egg activation. In addition to these fundamental insights, our results provide valuable resources for future studies. 42 samples analyzed using RNA-seq, ribosome footprint profiling, and PAL-seq.

2016-08-08 | E-GEOD-83616 | biostudies-arrayexpress

mRNA Poly(A)-tail Changes Specified by Deadenylation Broadly Reshape Translation in Drosophila Oocytes and Early Embryos

Project description:Because maturing oocytes and early embryos lack transcription, posttranscriptional regulatory processes must control their development. To better understand this control, we profiled translational efficiencies and poly(A)-tail lengths throughout Drosophila oocyte maturation and early embryonic development. The correspondence between translational-efficiency changes and tail-length changes indicated that tail-length changes broadly reshape translational activity until gastrulation, when this coupling disappears. Relative changes were largely retained in the absence of poly(A)-tail lengthening, which indicated that selective poly(A)-tail shortening primarily specifies the changes. Many translational changes depended on PAN GU and Smaug, and both acted primarily through tail-length changes. Our results also revealed tail-length–independent mechanisms of translational control that repressed translation regardless of tail-length changes during oocyte maturation, maintained translation despite tail-length shortening during oocyte maturation, and prevented detectable translation of bicoid and several other mRNAs before egg activation. In addition to these fundamental insights, our results provide valuable resources for future studies.

2016-08-08 | GSE83616 | GEO

Genome-wide analysis of mRNA polyadenylation and translation during vertebrate oocyte maturation

Project description:Changes in gene expression are required to orchestrate changes in cell state during development. Most cells change patterns of gene expression through transcriptional regulation. In contrast, oocytes are transcriptionally silent and use changes in mRNA poly-A tail length to control protein production. Recent technical advances have enabled genome-wide measurement of poly-A tail length. Poly-A tail lengthening is correlated with translational activation and poly-A tail shortening is correlated with translational repression at a global level during early development. However, it is not clear how poly-A tail changes affect mRNA translation at a global level during vertebrate oocyte maturation. We used TAIL-seq and polyribosome analysis to measure poly-A tail and translational changes during oocyte maturation in Xenopus laevis. We found that the transcriptome undergoes large-scale poly-A and translational changes during oocyte maturation and that poly-A tail length and translation are well-correlated. Interestingly, we found that poly-A tail changes precede translation changes. Additionally, we identified a family of U-rich sequence elements that are enriched near the polyadenylation signal of polyadenylated and translationally activated mRNAs. Interestingly, we found that cytoplasmic polyadenylation is not sufficient to activate translation, which requires a specific density and spacing of U-rich elements. Collectively, our data shows that changes in mRNA polyadenylation are the dominant mechanism controlling protein expression during vertebrate oocyte maturation and that these changes are controlled by a group of cis-acting sequence elements. Our results provide insight into mechanisms of translational control in oocytes and identify novel proteins important for the completion of meiosis.

2020-01-14 | GSE134537 | GEO

Transcriptome-wide profiling of poly(A)-tail length, translation efficiency and mRNA stability using TED-seq, mRNA-seq, Ribo-seq and PRO-seq in ER stress conditions

Project description:We report systematical profiling of translation efficiency and mRNA stability dependent on the dynamics of poly(A)-tail length in stress conditions of human cells. In this study, we developed a new feasible method measuring poly(A)-tail length called TED-seq and applied it to investigate the change of mRNA's poly(A)-tail lengths in ER stress pharmacologically induced by thapsigargin (THAP). Combined with other global RNA analyses such as RNA-seq, Ribo-seq and PRO-seq, we observed that ER stress induced lenthening poly(A)-tail length, in particular of ER-stress-regulators, upon ER stress. More specifically, these mRNAs are translationally de-repressed and more stabilized based on increase in poly(A)-tail length. We also identified that insoluble fractions which include stress-induced RNA-granules have overall shorter length of poly(A) tail. Taken together, our data suggest that poly(A)-tail lengths are dynamically regulated and influence both translation efficiency and mRNA stability in ER stress.

2018-01-01 | GSE103719 | GEO

Regulation of poly(A) tail and translation during the somatic cell cycle

Project description:Poly(A) tails are critical for mRNA stability and translation. However, recent studies have challenged this view, showing that poly(A) tail length and translation efficiency are decoupled in non-embryonic cells. Using TAIL-seq and ribosome profiling, we investigate poly(A) tail dynamics and translational control in the somatic cell cycle. We find dramatic changes in poly(A) tail lengths of cell cycle regulatory genes like CDK1, TOP2A, and FBXO5, explaining their translational repression in M phase. We also find that poly(A) tail length is coupled to translation when the poly(A) tail is <20 nucleotides. However, as most genes have >20 nucleotide poly(A) tails, their translation is regulated mainly via poly(A) tail length-independent mechanisms during the cell cycle. Specifically, we find that terminal oligopyrimidine (TOP) tract-containing transcripts escape global translational suppression in M phase and are actively translated. Our quantitative and comprehensive data provide a revised view of translational control in the somatic cell cycle.

2016-04-04 | GSE79664 | GEO

Regulation of poly(A) tail and translation during the somatic cell cycle

2016-04-04 | E-GEOD-79664 | biostudies-arrayexpress

An extended wave of global mRNA deadenylation sets up a switch in translation regulation across the mammalian oocyte-to-embryo transition

Project description:The oocyte-to-embryo transition (OET) occurs in the absence of new transcription and relies on post-transcriptional gene regulation, including translational control by mRNA poly(A) tail regulation, where cytoplasmic polyadenylation activates translation and deadenylation leads to translational repression and decay. However, how the transcriptome-wide landscape of mRNA poly(A) tails shapes translation across the OET in mammals remains unknown. Here, we performed long-read RNA sequencing to uncover poly(A) tail lengths and mRNA abundance transcriptome-wide in mice across five stages of development from oocyte to embryo. Integrating these data with recently published ribosome profiling data, we demonstrate that poly(A) tail length is coupled to translational efficiency across the entire OET. We uncover an extended wave of global deadenylation during fertilization, which sets up a switch in translation control between the oocyte and embryo. In the oocyte, short-tailed maternal mRNAs that resist deadenylation in the oocyte are translationally activated, whereas large groups of mRNAs deadenylated without decay in the oocyte are later readenylated to drive translation activation in the early embryo. Our findings provide an important resource and insight into the mechanisms by which cytoplasmic polyadenylation and deadenylation dynamically shape poly(A) tail length in a stage-specific manner to orchestrate development from oocyte to embryo in mammals.

2024-03-14 | GSE228001 | GEO

mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading [polysome fractionation]

Project description:Translation of TOP mRNAs encoding protein synthesis machinery is strictly regulated by an amino acid sensing mTOR pathway. However, its regulatory mechanism remains elusive. Here, we demonstrate that TOP mRNA translation positively correlates with its poly(A) tail length under mTOR active/amino acid-rich condition, suggesting that TOP mRNAs are post-transcriptionally controlled by poly(A) tail length regulation. Consistent with this, tail length of TOP mRNAs dynamically fluctuates in response to amino acid availability. Poly(A) tail shortens under mTOR active/ amino acid-rich condition, whereas the long-tailed TOP mRNAs accumulate under mTOR inactive/amino acid-starved (AAS) condition. An RNA-binding protein LARP1 that specifically binds to TOP mRNAs is indispensable for the process. We also show that LARP1 interacts with non-canonical poly(A) polymerases, PAPD4, PAPD5 and PAPD7 and induces post-transcriptional polyadenylation of the target when tethered to the mRNA. Our findings illustrate that LARP1 contributes to the selective accumulation of TOP mRNAs with long poly(A) tail under AAS, resulting in accelerated ribosomal loading onto TOP mRNAs for the resumption of translation after AAS.

2022-09-22 | GSE145744 | GEO

mTOR- and LARP1-dependent regulation of TOP mRNA poly(A) tail and ribosome loading [LARP1 KD, Torin1]

2022-09-19 | GSE137807 | GEO

Control of poly(A)-tail length and translation in vertebrate oocytes and early embryos

Project description:During oocyte maturation and early embryonic development, poly(A)-tail lengths strongly influence mRNA translation. However, how tail lengths are controlled at different developmental stages has been unclear. Here, we performed tail-length and translational profiling of mRNA reporter libraries (each with > 10 million 3ʹ-UTR sequence variants) in frog oocytes and embryos, and fish embryos. These analyses revealed that the UUUUA motif specifies cytoplasmic polyadenylation and identified diverse context features that modulate the activity of this 5-mer. Additional sequence motifs drive stage-specific deadenylation in embryos, and UUUUA and C-rich motifs drive tail-length-independent translational repression in oocytes. A neural network model accurately predicts tail-length change during oocyte maturation in frogs, mice, and humans. Analyses of human sequence variants showed that those predicted to disrupt tail-length control have been under negative selection, implying that our insights into control of poly(A)-tail length and translation have implications for human health and fertility.

2024-02-15 | GSE241107 | GEO

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