Transcript buffering and 3ʹUTR lengthening are shaped during human neurodevelopment by shifts in mRNA stability and microRNA load
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ABSTRACT:
PROVIDER: PRJNA878683 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21497000.fastq.gz | Fastqsanger.gz | |||
| SRR21497001.fastq.gz | Fastqsanger.gz | |||
| SRR21497002.fastq.gz | Fastqsanger.gz | |||
| SRR21497003.fastq.gz | Fastqsanger.gz | |||
| SRR21497004.fastq.gz | Fastqsanger.gz |
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Project description:The change in abundance of individual mRNAs as cells differentiate through neurodevelopmental stages is generally attributed to transcription level alterations while the potential contribution of mRNA half-life is commonly overlooked. While some genes are regulated solely by transcription, others may be regulated by mRNA half-life only, or genes with changed transcription rates could be buffered by compensating half-life decreases or even boosted by amplifying half-life increases. In addition, during neurodevelopment there is widespread 3ʹUTR lengthening that could be shaped by differential shifts in the stability of transcript isoforms. Here we measure transcription rate and mRNA half-life changes during induced Pluripotent Stem Cell-derived neuronal development using RATE-seq at the resolution of gene isoforms. We found that during transitions to progenitor and neuron stages, transcript buffering occurs in up to half of all genes. Half-life only changes are observed in as many genes as transcription rate only changes, and almost 10% of genes exhibit transcript boosting. Global mRNA half-life decreases two-fold in neurons relative to iPSCs. The observed mRNA destabilization differentially affects gene isoforms and contributes to 3ʹUTR lengthening. Small RNA sequencing further captured an increase in microRNA copy number per cell. We propose that mRNA destabilization and 3ʹUTR lengthening are driven in part by an increase in microRNA load. Our findings identify mRNA stability mechanisms in human neurodevelopment that regulate gene and isoform level abundance and provide a precedent for similar post-transcriptional regulatory events as other tissues develop.
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Project description:Regulation of translationduring early human development is poorly understood anditsdysregulation is associated with disease. To discover shifts in mRNA ribosomal engagement (RE) that occur during human neurodevelopment and disease, we used parallel TRAPSeq and RNASeq on control and Rett syndrome (RTT) human induced pluripotent stem cells,neural progenitor cells and cortical neurons. We found 30% of transcribed genes were translationally regulatedincluding key gene sets (neurodevelopment, transcription and translation factors, glycolysis). Neurons more efficiently translated global mRNAs,had longer 3`UTRs and RE correlated with RNA-binding protein motif composition.In contrast, RTT neurons had reduced global translation,compromised mTOR signalingand 2100 genes were translationally dysregulated. NEDD4L E3-ubiquitin ligasewas most translationally impaired, and its protein targets accumulatedin RTT neurons. Our findings reveal a dynamic translatome in neurodevelopment, show that MECP2 regulatestranslationandubiquitin enzymes in neurons, and provide novel insight into altered proteostasis that may have therapeutic implications for RTT.
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Project description:To help elucidate mechanistic differences between lengthening and shortening muscle contractions we compared changes in gene expression within 24 h of an acute bout of each type of contraction in the quadriceps. Three healthy young men performed shortening contractions with one leg while the contralateral leg performed lengthening contractions. Biopsies were taken from both legs before exercise, 3, 6, and 24 h afterwards. Expression profiling was performed using a custom-made Affymetrix MuscleChip containing probesets of approximately 3,300 known genes and ESTs expressed in skeletal muscle. We identified 49 genes differentially regulated between the lengthening and shortening contractions. Using unsupervised hierarchical clustering, we identified four distinct clusters, three of which corresponded to unique functional categories (protein synthesis, stress response/early growth, and sarcolemmal structure). The results suggest distinct molecular pathways as early as 3 h post exercise. The molecular differences might contribute to mechanisms underlying the physiological adaptations seen with training using the two modes of exercise. Keywords: Time Series Design The hypothesis of the current study was that genes involved in hypertrophy will be differentially regulated between the two types of contractions.
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Project description:To help elucidate mechanistic differences between lengthening and shortening muscle contractions we compared changes in gene expression within 24 h of an acute bout of each type of contraction in the quadriceps. Three healthy young men performed shortening contractions with one leg while the contralateral leg performed lengthening contractions. Biopsies were taken from both legs before exercise, 3, 6, and 24 h afterwards. Expression profiling was performed using a custom-made Affymetrix MuscleChip containing probesets of approximately 3,300 known genes and ESTs expressed in skeletal muscle. We identified 49 genes differentially regulated between the lengthening and shortening contractions. Using unsupervised hierarchical clustering, we identified four distinct clusters, three of which corresponded to unique functional categories (protein synthesis, stress response/early growth, and sarcolemmal structure). The results suggest distinct molecular pathways as early as 3 h post exercise. The molecular differences might contribute to mechanisms underlying the physiological adaptations seen with training using the two modes of exercise. Keywords: Time Series Design
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Project description:Aneuploidy, i.e., variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segment (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined, is the leading cause of miscarriages and mental retardations and a hallmark of cancer. Despite their documented importance in disease the effects of aneuploidies on the transcriptome remains largely unknown. Here we have examined the expression output in seven deficiency heterozygotes as single deficiencies and in all pairwise combinations. The results show that genes in one copy are buffered, i.e., are expressed above the expected 50% expression level compared to wild type and the buffering is general and not influenced by additional haploid regions. Long genes are significantly better buffered than short genes and our analysis suggests that gene length is the primary determinant for the degree of buffering. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Our results suggest that proteolysis is a general response induced by aneuploidy.
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Project description:Aneuploidy, i.e., variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segment (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined, is the leading cause of miscarriages and mental retardations and a hallmark of cancer. Despite their documented importance in disease the effects of aneuploidies on the transcriptome remains largely unknown. Here we have examined the expression output in seven deficiency heterozygotes as single deficiencies and in all pairwise combinations. The results show that genes in one copy are buffered, i.e., are expressed above the expected 50% expression level compared to wild type and the buffering is general and not influenced by additional haploid regions. Long genes are significantly better buffered than short genes and our analysis suggests that gene length is the primary determinant for the degree of buffering. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Our results suggest that proteolysis is a general response induced by aneuploidy. We prepared total RNA from flies heterozygous for seven different deletions, Df(3R)ED10953, Df(2L)ED4559, Df(2R)ED1770, Df(2R)ED1612, Df(2L)ED3, Df(3R)ED5071 or Df(3R)ED7665 in two or three single biological replicates or in pairwise combinations, as well as from six biological replicates of wild type control flies.
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