High-throughput discovery of post-transcriptional cis-regulatory elements
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA302654 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2924291.fastq.gz | Fastqsanger.gz | |||
| SRR2924292.fastq.gz | Fastqsanger.gz | |||
| SRR2924293.fastq.gz | Fastqsanger.gz | |||
| SRR2924294.fastq.gz | Fastqsanger.gz | |||
| SRR2924295.fastq.gz | Fastqsanger.gz |
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Project description:Post-transcriptional gene regulation controls the amount of a protein produced from an individual mRNA transcript by altering mRNA decay and translation rates. Many putative post-transcriptional cis-regulatory elements have been identified from computational, molecular biology, and biochemical studies studies; however, identifying which sequence elements are sufficient to regulate expression remains challenging. We created a high-throughput, cell-based screen that tested the post-transcriptional regulatory potential for thousands of short sequence elements. Sequences with known effects have the expected performance in this screen, showing this methodology is robust. Hundreds of novel short sequences were identified as being able to alter gene expression, both by increasing and decreasing protein production from the fluorescence reporter, and we validated the effects for fifty of these sequences. Importantly, sequences discovered in this screen are conserved in human 3′UTRs, and furthermore, the sequences can regulate expression in the context of those endogenous 3′UTRs. Hundreds of previously unknown post-transcriptional cis-regulatory elements exist, many of which increase gene expression. These results suggest that each human 3′UTR has many small cis-regulatory elements that interact with RNA binding proteins, and these interactions control the fate of an mRNA transcript.
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Project description:Post-transcriptional gene regulation controls the amount of a protein produced from an individual mRNA transcript by altering mRNA decay and translation rates. Many putative post-transcriptional cis-regulatory elements have been identified from computational, molecular biology, and biochemical studies studies; however, identifying which sequence elements are sufficient to regulate expression remains challenging. We created a high-throughput, cell-based screen that tested the post-transcriptional regulatory potential for thousands of short sequence elements. Sequences with known effects have the expected performance in this screen, showing this methodology is robust. Hundreds of novel short sequences were identified as being able to alter gene expression, both by increasing and decreasing protein production from the fluorescence reporter, and we validated the effects for fifty of these sequences. Importantly, sequences discovered in this screen are conserved in human 3?UTRs, and furthermore, the sequences can regulate expression in the context of those endogenous 3?UTRs. Hundreds of previously unknown post-transcriptional cis-regulatory elements exist, many of which increase gene expression. These results suggest that each human 3?UTR has many small cis-regulatory elements that interact with RNA binding proteins, and these interactions control the fate of an mRNA transcript.
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Project description:Post-transcriptional gene regulation controls the amount of protein produced from an individual mRNA by altering rates of decay and translation. Many sequence elements that direct post-transcriptional regulation have been found; in mammals, most such elements are located within the 3' untranslated regions (3'UTRs). Comparative genomic studies demonstrate that mammalian 3'UTRs contain extensive conserved sequence tracts, yet only a small fraction corresponds to recognized elements, implying that many additional novel elements exist. Despite a variety of computational, molecular, and biochemical approaches, identifying functional 3'UTRs elements remains difficult.We created a high-throughput cell-based screen that enables identification of functional post-transcriptional 3'UTR regulatory elements. Our system exploits integrated single-copy reporters, which are expressed and processed as endogenous genes. We screened many thousands of short random sequences for their regulatory potential. Control sequences with known effects were captured effectively using our approach, establishing that our methodology was robust. We found hundreds of functional sequences, which we validated in traditional reporter assays, including verifying their regulatory impact in native sequence contexts. Although 3'UTRs are typically considered repressive, most of the functional elements were activating, including ones that were preferentially conserved. Additionally, we adapted our screening approach to examine the effect of elements on RNA abundance, revealing that most elements act by altering mRNA stability.We developed and used a high-throughput approach to discover hundreds of post-transcriptional cis-regulatory elements. These results imply that most human 3'UTRs contain many previously unrecognized cis-regulatory elements, many of which are activating, and that the post-transcriptional fate of an mRNA is largely due to the actions of many individual cis-regulatory elements within its 3'UTR.
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Project description:Decoding post-transcriptional regulatory programs underlying gene expression is a crucial step toward a predictive dynamical understanding of cellular state transitions. Despite recent systematic efforts, the sequence determinants of such mechanisms remain largely uncharacterized. An important obstacle in revealing these elements stems from the contribution of local secondary structures in defining interaction partners in a variety of regulatory contexts, including but not limited to transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (e.g. human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. We have developed a computational framework based on context-free grammars and mutual information that systematically explores the immense space of structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behavior. The application of this framework to genome-wide mammalian mRNA stability data revealed eight highly significant elements with substantial structural information, for the strongest of which we showed a major role in global mRNA regulation. Through biochemistry, mass-spectrometry, and in vivo binding studies, we identified HNRPA2B1 as the key regulator that binds this element and stabilizes a large number of its target genes. Ultimately, we created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach can also be employed to reveal the structural elements that modulate other aspects of RNA behavior. This SuperSeries is composed of the following subset Series: GSE35749: sRSM1 synthetic decoy vs. scrambled transfections in MDA-MB-231 cells GSE35753: HNRPA2B1 RIP-chip GSE35756: Whole-genome decay rate measurements in MDA-MB-231 cells transfected with HNRPA2B1 siRNAs versus controls GSE35757: siRNA-mediated HNRPA2B1 knock-down in MDA-MB-231 cells GSE35799: HNRPA2B1 HITS-CLIP Refer to individual Series
2012-02-28 | E-GEOD-35800 | biostudies-arrayexpress