The 3’ Untranslated Region (3’UTR) Coding Sequence of PHO84, Rather Than the Antisense RNA, Promotes Gene Repression
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ABSTRACT:
PROVIDER: PRJNA944239 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23852610_1.fastq.gz | Fastqsanger.gz | |||
| SRR23852610_2.fastq.gz | Fastqsanger.gz | |||
| SRR23852611_1.fastq.gz | Fastqsanger.gz | |||
| SRR23852611_2.fastq.gz | Fastqsanger.gz | |||
| SRR23852612_1.fastq.gz | Fastqsanger.gz |
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Project description:We provide evidence that the model of antisense-mediated repression of PHO84 gene is not correct, and that the 3’UTR of PHO84 exhibits a repressive effect on the sense transcript. We also provide a list of trans-acting elements promoting 3’UTR-dependent repression. Such information can be taken further to possibly identify key players in human diseases arising from gene expression dysregulation.
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Project description:PHO84 is a budding yeast gene reported to be negatively regulated by its cognate antisense transcripts both in cis and in trans. In this study, we performed Transient-transcriptome sequencing (TT-seq) to investigate the correlation of sense/antisense pairs in a dbp2Δ strain and found over 700 sense/antisense pairs, including PHO84, to be positively correlated, contrasting the prevailing model. To define what mechanism regulates the PHO84 gene and how this regulation could have been originally attributed to repression by the antisense transcript, we conducted a series of molecular biology and genetics experiments. We now report that the 3' untranslated region (3'UTR) of PHO84 plays a repressive role in sense expression, an activity not linked to the antisense transcripts. Moreover, we provide results of a genetic screen for 3'UTR-dependent repression of PHO84 and show that the vast majority of identified factors are linked to negative regulation. Finally, we show that the PHO84 promoter and terminator form gene loops which correlate with transcriptional repression, and that the RNA-binding protein, Tho1, increases this looping and the 3'UTR-dependent repression. Our results negate the current model for antisense non-coding transcripts of PHO84 and suggest that many of these transcripts are byproducts of open chromatin.
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Project description:Mature messenger RNAs (mRNAs) consist of coding sequence (CDS) and 5’ and 3’ untranslated regions, typically expected to show similar abundance within a given neuron. Examining mRNA from defined neurons we unexpectedly show extremely common unbalanced expression of cognate 3’ UTR and CDS sequences, observing many genes with high UTR relative to CDS, and others with high CDS to UTR. By in situ hybridization 19 of 19 genes examined show a broad range of UTR to CDS expression ratios in different neurons and other tissues. These ratios may be spatially graded or change with developmental age, but are consistent across animals. Further, for two genes examined, a UTR to CDS ratio above a particular threshold in any given neuron correlated with reduced or undetectable protein expression. Our findings raise questions about the role of isolated UTR sequences in regulation of protein expression, and highlight the importance of separately examining UTR and CDS sequences in gene expression analyses.
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Project description:The capacity of cells to retain a memory of previous signals enables them to adopt unique cell fates and adjust to their surrounding environment. The underlying gene expression memory can arise from mutual repression of two genes, forming a toggle switch. Such mutual repression may occur at antisense loci, where two convergently oriented genes repress each other in cis. Under which conditions antisense transcription can generate expression memory remains poorly understood. To address this question, we combine mathematical modeling, genomics and a synthetic biology approach. Through simulations we show that stable memory can emerge, if both genes in an antisense pair transcribe through the convergent promoter and induce a stable repressive chromatin state. Genome-wide analysis of nascent transcription further supports antisense-mediated promoter repression with promoter-overlapping antisense gene pairs exhibiting mutually exclusive expression. Through constructing a synthetic antisense locus in mouse embryonic stem cells (mESCs) we then show that such a locus architecture can indeed maintain a memory of a transient stimulus. Mutual repression and the capacity for memory formation are elevated, when mESCs differentiate, showing that epigenetic memory is a cell type-specific property. Our finding that stem cells adapt their ability to remember stimuli as they differentiate might help to elucidate how stemness is maintained.
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Project description:Pervasive transcription generates mainly unstable non-coding transcripts. Although a few examples of pervasive antisense have been shown to mediate gene regulation by transcriptional interference, whether pervasive transcription has a general functional role or merely represents transcriptional noise remains to be determined. In a mutant context that revealed pervasive transcripts, we characterized more than 800 antisenses genome wide and analysed the corresponding sense mRNA behaviour. We observed that antisense non-coding transcription is commonly found associated with genes tightly repressed during the exponential phase with an opposite level of mRNA and the associated antisense. This suggested that antisense transcription might participate to a tight repression of genes during the exponential phase. We thus specifically interrupted the antisense transcription of a subset of genes, and found that it resulted in a de-repression of the corresponding mRNAs. We further validated that this repression acts in cis through a transcriptional interference mechanism, which involves several chromatin modification factors. Transcription interference is observed for the first time as a general mean of gene regulation between cellular states.
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