A DNA Repair Pathway Can Regulate Transcriptional Noise to Promote Cell Fate Transitions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA734629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14713300.fastq.gz | Fastqsanger.gz | |||
| SRR14713301.fastq.gz | Fastqsanger.gz | |||
| SRR14713302.fastq.gz | Fastqsanger.gz | |||
| SRR14713303.fastq.gz | Fastqsanger.gz | |||
| SRR14713304.fastq.gz | Fastqsanger.gz |
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Project description:Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental but, in many disciplines, fluctuations are exploited for benefit (e.g., dither). We show here that DNA base-excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA-repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean-expression levels. This amplified expression noise originates from shorter duration, higher intensity, transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels and this mechanism, which we term Discordant Transcription through Repair (DiThR), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.
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Project description:Stochastic fluctuations in gene expression ("noise") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as "discordant transcription through repair" ("DiThR," which is pronounced "dither"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.
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Project description:Alternative mRNA isoforms and long noncoding RNAs (lncRNA) make up a large fraction of the transcriptome and play key functions in cell-fate programming. These transcripts often initiate upstream of coding gene promoters from alternative transcription start sites (TSS) where they can regulate gene expression in cis through transcription-coupled chromatin alterations. How, when and where transcription of alternative cis-acting RNAs regulates local gene expression remains poorly understood. Here, we use a high-resolution quantitative approach to study alternative TSS and transcript end site (TES) usage during three different cell fate transitions in yeast: entry into gametogenesis, commitment to meiotic divisions and return to vegetative growth. We propose that an alternative transcriptome of mRNA isoforms and lncRNAs shapes local gene expression during cell fate transitions. Hence, changes in the types and proportions of different RNAs transcribed at a locus are important inputs for gene expression at distinct stages of development.
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