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Systematic identification of regulatory elements in conserved 3’-untranslated regions of human transcripts

ABSTRACT: We present a combined experimental/computational technology to reveal a catalogue of functional regulatory elements embedded in 3’UTRs of human transcripts. We used a bidirectional reporter system coupled with flow cytometry and high-throughput sequencing to measure the effect of short, non-coding vertebrate-conserved RNA sequences on transcript stability and translation. Information-theoretic motif analysis of the resulting sequence-to-gene-expression mapping revealed linear and structural RNA cis-regulatory elements that positively and negatively modulate the post-transcriptional fates of human transcripts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55396 | GEO | 2014/03/21

SECONDARY ACCESSION(S): PRJNA239465

REPOSITORIES: GEO

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Systematic identification of regulatory elements in conserved 3’-untranslated regions of human transcripts

Project description:We present a combined experimental/computational technology to reveal a catalogue of functional regulatory elements embedded in 3’UTRs of human transcripts. We used a bidirectional reporter system coupled with flow cytometry and high-throughput sequencing to measure the effect of short, non-coding vertebrate-conserved RNA sequences on transcript stability and translation. Information-theoretic motif analysis of the resulting sequence-to-gene-expression mapping revealed linear and structural RNA cis-regulatory elements that positively and negatively modulate the post-transcriptional fates of human transcripts. We explored the functional role of 16332 short human 3'UTR sequences (C3U Library) evolutionarily conserved with P. troglodytes, M. musculus and G. gallus. For sorting the C3U library into subpopulations, we gated the population using FACS into bins each containing 10% of the total number of cells. We collected cells for the top four high expression bins (H10, H20, H30, H40) and the bottom four low expression bins (L10, L20, L30, L40) Multiple samples (C3U library subpopulations) were pooled for each illumina index (decribed n the 'library construction protocol' field). For example, six samples (A-L10 I & II, B-L10 I & II, A-L20 I & II) were all pooled in illumina index CGATGTAT. Therefore, each individual fastq file corresponds to multiple samples. The individual samples were sorted in the processing step using identifiers inside the sequence reads. One single pooled sample was run on both lanes (the extra lane was run for additional reads). The expression level (H: high, L:low or background) and library replicates (A or B) of the pooled library subpopulations are indicated in the sample title.

2014-03-21 | E-GEOD-55396 | biostudies-arrayexpress

Functional and structural basis of extreme conservation in vertebrate 5’ untranslated regions [dmsmap1d]

Project description:The lack of knowledge about extreme conservation in genomes remains a major gap in our understanding of the evolution of gene regulation. Here, we reveal an unexpected role of extremely conserved 5’UTRs in non-canonical translational regulation that is linked to the emergence of essential developmental features in vertebrate species. Endogenous deletion of conserved elements within these 5’UTRs decreased gene expression, and extremely conserved 5’UTRs possess cis-regulatory elements that promote cell-type specific regulation of translation. We further developed in-cell mutate-and-map (icM2), a novel methodology that maps RNA structure inside cells. Using icM2, we determined that an extremely conserved 5’UTR encodes multiple alternative structures and that each single nucleotide within the conserved element maintains the balance of alternative structures important to control the dynamic range of protein expression. These results explain how extreme sequence conservation can lead to RNA-level biological functions encoded in the untranslated regions of vertebrate genomes.

2021-01-30 | GSE155653 | GEO

Functional and structural basis of extreme conservation in vertebrate 5’ untranslated regions [icm2]

2021-01-30 | GSE155655 | GEO

DHX36 resolves G-rich structures in mRNA untranslated region to allow their translation [PAR-CLIP-seq]

Project description:DHX36 is a ATP-dependent, 3´-5´ RNA helicase of the DEAH family. Previous publications reported this helicase to associate with AU-rich elements and to specifically unwind G-quadruplex structures. Here, we performed PAR-CLIP in duplicates to specifically crosslink DHX36 and helicase-dead DHX36 E335A to its RNA binding targets in HEK293 cells. After sequencing and mapping to the human genome at nucleotide-resolution level we combined sequencing reads to a total of over 60000 binding clusters on more than 9000 transcripts. Distribution analyses revealed that DHX36 binds mainly to CDSs and 3´UTRS of mRNAs. Also, a G-rich binding motif for DHX36 was identified.

2019-07-01 | GSE105171 | GEO

Atlas of nascent RNA transcripts reveals high confidence enhancer associated bidirectionals linked with genes across different tissue types

Project description:Gene transcription is controlled and modulated by enhancers and promoters. These regions are abundant in non-coding bidirectional RNA transcripts which have been used as a read-out of enhancer and promoter activity. Using nascent RNA transcription data across hundreds of samples, we identified 500,000 regions of bidirectional transcription and linked the transcripts to gene targets. The identified bidirectional and gene pairs are associated with diseases associated SNPs and these pairs are links in 3D genome space. We present these resources as an SQL database which allows for further investigation and understanding of how gene transcription is regulated.

2023-04-20 | GSE227931 | GEO

Progressive lengthening of 3' untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development

Project description:The 3' untranslated regions (3' UTRs) of mRNAs contain cis-acting elements for posttranscriptional regulation of gene expression. Here, we report that mouse genes tend to express mRNAs with longer 3' UTRs as embryonic development progresses. This global regulation is controlled by alternative polyadenylation and coordinates with initiation of organogenesis and aspects of embryonic development, including morphogenesis, differentiation, and proliferation. Using myogenesis of C2C12 myoblast cells as a model, we recapitulated this process in vitro and found that 3' UTR lengthening is likely caused by weakening of mRNA polyadenylation activity. Because alternative 3' UTR sequences are typically longer and have higher AU content than constitutive ones, our results suggest that lengthening of 3' UTR can significantly augment posttranscriptional control of gene expression during embryonic development, such as microRNA-mediated regulation. Two biological replicates of C2C12 growth and differentiation conditions, repesctively

2010-08-31 | E-GEOD-23871 | biostudies-arrayexpress

1 A post-transcriptional regulatory code for mRNA stability dur-ing the maternal-to-zygotic transition

Project description:Post-transcriptional regulation is crucial to shape gene expression. During the Maternal-to-Zygotic transition (MZT), thousands of maternal transcripts are regulated upon fertili-zation and genome activation. Transcript stability can be influenced by cis-elements and trans-factors, but how these inputs are integrated to determine the overall mRNA stability is unclear. Here, we show that most transcripts are under combinatorial regulation by multiple decay pathways. Characterization of the cis-regulatory motifs revealed that nu-cleotide composition bias characteristic of 3’-UTRs poly-U is associated with mRNA stability. In contrast, miR-430, CCUC, CUGC, elements appeared as the main destabiliz-ing motifs, with miR-430 and UAUUUAU (ARE) sequences causing mRNA deadenyla-tion depending on the activation of the genome. We comprehensively identify RNA-protein interactions across the transcriptome during MZT, and their associated regulatory activity. We find that poly-U binding proteins are preferentially associated with 3’-UTR sequences and stabilizing motifs. Analysis of differentially regulated regions revealed antagonistic sequence contexts for poly-C and poly-U binding proteins that shape protein binding and magnitude of regulation across the transcriptome. Finally, we integrate these regulatory motifs into a machine learning model, able to predict the stability of mRNA reporters in vivo. Our findings reveal how mechanisms of post-transcriptional regulation are coordinated to direct changes in mRNA stability within the early embryo.

2020-05-26 | PXD009514 | Pride

Systematic Interrogation of Human Promoters

Project description:Despite much research, our understanding of the architecture and cis-regulatory elements of human promoters is still lacking. Here, we devised a high-throughput assay to quantify the activity of ~15,000 fully designed sequences that we integrated and expressed from a fixed location within the human genome. We used this method to investigate thousands of native promoters and pre-initiation complex (PIC) binding regions followed by in-depth characterization of the sequence motifs underlying promoter activity including core promoter elements and TF binding-sites. We find that core promoters drive transcription mostly unidirectionally, and that sequences originating from promoters exhibit stronger activity than those originating from enhancers. Testing multiple synthetic configurations of core promoter elements, we dissect the motifs that positively and negatively regulate transcription as well as the effect of their combinations and distances, including a 10bp periodicity in the optimal distance between the TATA and the Initiator. By comprehensively screening 133 TF binding-sites, we find that in contrast to core promoters, TF binding-sites maintain similar activity levels in both orientations supporting a model by which divergent transcription is driven by two distinct unidirectional core promoters sharing bidirectional TF binding-sites. Finally, we find a striking agreement between the effect of binding site multiplicity of individual TFs in our assay and their tendency to appear in homotypic clusters throughout the genome. Overall, our study systematically assays the elements that drive expression in core- and proximal- promoter regions and shed light on organization principles of regulatory regions in the human genome.

2018-08-08 | GSE118242 | GEO

Multiple polyadenylation signals and 3' untranslated sequences are conserved between chicken and human cellular myosin II transcripts.

Project description: Not available

| S-EPMC5952193 | biostudies-literature

Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (PLUMAGE)

Project description:The functional consequences of cancer patient-derived genetic variants within the 5’ untranslated regions (UTRs) on a genome-wide scale and their effects on mRNA transcript and translation levels are poorly understood. To systematically interrogate the mutational landscape of 5’ UTRs across cancer patients with localized to metastatic disease, we analyzed the genomes of 226 prostate cancer patients and observed thousands of mutations, many of which impact known cis-regulatory elements. We developed a high-throughput multi-layer massively parallel sequencing-based method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to simultaneously quantify the effects of 545 5’ UTR somatic mutations across recurrently mutated or cancer-related genes from our patient cohort. Our method enabled unprecedented insights into how 5’ UTR mutations can control multiple levels of gene expression simultaneously. In particular, we identified 190 mutations that significantly altered 5’ UTR function, either by creating new DNA binding elements, disrupting known translation regulatory motifs, or simultaneously impacting both transcript levels and mRNA translation. Furthermore, we also determined that 5’ UTR mutations to the MAP kinase signaling pathway are significantly associated with early metastasis. This study is the first to comprehensively interrogate the functional 5’ UTR mutational landscape of a human cancer revealing the importance of untranslated regions in regulating multiple levels of oncogenic gene expression and provides a high-throughput functional genomics solution applicable to many genetically driven diseases.

2021-05-17 | GSE149487 | GEO

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