Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA789909 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17264655.fastq.gz | Fastqsanger.gz | |||
| SRR17264656.fastq.gz | Fastqsanger.gz | |||
| SRR17264657.fastq.gz | Fastqsanger.gz | |||
| SRR17264658.fastq.gz | Fastqsanger.gz | |||
| SRR17264659.fastq.gz | Fastqsanger.gz |
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Project description:Models of MECP2 dysfunction in Rett syndrome (RTT) assume that transcription rate changes directly correlate with altered steady-state mRNA levels. However, limited evidence suggests that transcription rate changes are buffered by poorly understood compensatory post-transcriptional mechanisms. Here we measure transcription rate and mRNA half-life changes in RTT patient neurons using RATE-seq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate only or half-life only and are buffered when both are changed. We utilized classifier models to understand the direction of transcription rate changes based on gene-body DNA sequence, and combined frequencies of three dinucleotides were better predictors than contributions by CA and CG. MicroRNA and RNA-Binding Protein (RBP) motifs were enriched in 3ʹUTRs of genes with half-life changes. Motifs for nuclear localized RBPs were enriched on buffered genes with increased transcription rate. Our findings identify post-transcriptional mechanisms in humans and mice that alter half-life only or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder.
2023-01-27 | GSE191168 | GEO
Project description:Transcriptional changes in Rett syndrome (RTT) are assumed to directly correlate with steady-state mRNA levels, but limited evidence in mice suggests that changes in transcription can be compensated by post-transcriptional regulation. We measure transcription rate and mRNA half-life changes in RTT patient neurons using RATEseq, and re-interpret nuclear and whole-cell RNAseq from Mecp2 mice. Genes are dysregulated by changing transcription rate or half-life and are buffered when both change. We utilized classifier models to predict the direction of transcription rate changes and find that combined frequencies of three dinucleotides are better predictors than CA and CG. MicroRNA and RNA-binding Protein (RBP) motifs are enriched in 3'UTRs of genes with half-life changes. Nuclear RBP motifs are enriched on buffered genes with increased transcription rate. We identify post-transcriptional mechanisms in humans and mice that alter half-life or buffer transcription rate changes when a transcriptional modulator gene is mutated in a neurodevelopmental disorder.
| S-EPMC10076348 | biostudies-literature
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.
2023-09-01 | GSE212990 | GEO
Project description:mRNA abundances are regulated by the opposing forces of transcription and decay, and yet how decay contributes to mRNA abundance regulation is largely unexplored. We addressed this question using genome-wide data on mRNA rates of abundance change, half-lives, and transcription rates of leaf cells responding to a transdifferentiation stimulusulus. Half-life regulation was common (22% of mRNAs underwent changes in half-life), but RNA abundance regulation by decay alone or by decay that supported transcriptional regulation was rare. Instead, most altered RNA half-lives opposed changes in transcription. Oppositionally regulated mRNAs were characterized by large changes in transcription and decay rates yet changes in mRNA abundances were either modest or undetectable, suggestive of RNA buffering. Oppositionally-regulated and buffered RNAs showed very similar dynamics, suggesting use of a common mechanism. The strongest contributions of RNA decay to RNA abundance regulation was in synergistically regulated transcripts, where rate changes in decay and transcription rates worked together to change RNA abundances.
2024-10-11 | GSE278544 | GEO
Project description:mRNA abundances are regulated by the opposing forces of transcription and decay, and yet how decay contributes to mRNA abundance regulation is largely unexplored. We addressed this question using genome-wide data on mRNA rates of abundance change, half-lives, and transcription rates of leaf cells responding to a transdifferentiation stimulusulus. Half-life regulation was common (22% of mRNAs underwent changes in half-life), but RNA abundance regulation by decay alone or by decay that supported transcriptional regulation was rare. Instead, most altered RNA half-lives opposed changes in transcription. Oppositionally regulated mRNAs were characterized by large changes in transcription and decay rates yet changes in mRNA abundances were either modest or undetectable, suggestive of RNA buffering. Oppositionally-regulated and buffered RNAs showed very similar dynamics, suggesting use of a common mechanism. The strongest contributions of RNA decay to RNA abundance regulation was in synergistically regulated transcripts, where rate changes in decay and transcription rates worked together to change RNA abundances.
2024-10-11 | GSE278543 | GEO
Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases. Total RNA was extracted from 100mg of postmortem brain tissue.
2015-11-24 | E-GEOD-75303 | biostudies-arrayexpress
Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases.
2015-11-24 | GSE75303 | GEO
Project description:Genome wide DNA methylation profiling of Rett syndrome monozygotic twins. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles in primary skin fibroblast cells from Rett syndrome monozygotic twins.
2012-12-27 | GSE43141 | GEO
Project description:Genome wide DNA methylation profiling of Rett syndrome monozygotic twins. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles in primary skin fibroblast cells from Rett syndrome monozygotic twins. Bisulphite converted DNA from the 2 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip
2012-12-27 | E-GEOD-43141 | biostudies-arrayexpress
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.
2012-04-05 | GSE34400 | GEO