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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE155656 | GEO | 2021/01/29

REPOSITORIES: GEO

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

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 | GSE155655 | GEO

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

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

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The structural basis for cohesin/CTCF anchored loops

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Genomic regions with distinct genomic distance conservation in vertebrate genomes.

Project description:BackgroundA number of vertebrate highly conserved elements (HCEs) have been detected and their genomic interval distances have been reported to be more conserved than protein coding genes among mammalian genomes. A characteristic of the human - non-mammalian comparisons is a bimodal distribution of relative distance difference of conserved consecutive HCE pairs; and it is difficult to attribute such profile to a random assortment. We therefore undertook an analysis of the human genomic regions confined by consecutive HCE pairs common to eight genomes (human, mouse, rat, chicken, frog, zebrafish, tetradon and fugu).ResultsAmong HCE pairs, we found that some consistently preserve highly conserved interval distance among genomes while others have relatively low distance conservation. Using a partition method, we detected two groups of inter-HCE regions (IHRs) with distinct distance conservation pattern in vertebrate genomes: IHR1s that are bordered by HCE pairs with relative small distance variation, and IHR2s with larger distance difference values. Compared to random background, annotated repeat sequences are significantly less frequent in IHR1s than IHR2s, which reflects a correlation between repeat sequences and the length expansion of IHRs. Both groups of IHRs are unexpectedly enriched in human indel (i.e. insertion and deletion) polymorphism-variations than random background. The correlation between the percentage of conserved sequence and human IHR length was stronger for IHR1 than IHR2. Both groups of IHRs are significantly enriched for CpG islands.ConclusionThe data suggest that subsets of HCE pairs may undergo different evolutionary paths in light of their genomic distance conservation, and that sets of genomic regions pertain to HCEs, as well as the region in which HCEs reside, should be treated as integrated domains.

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Massively parallel functional annotation of 3' untranslated regions.

Project description:Functional characterization of noncoding sequences is crucial for understanding the human genome and learning how genetic variation contributes to disease. 3' untranslated regions (UTRs) are an important class of noncoding sequences, but their functions remain largely uncharacterized. We developed a method for massively parallel functional annotation of sequences from 3' UTRs (fast-UTR) and used this approach to measure the effects of a total of >450 kilobases of 3' UTR sequences from >2,000 human genes on steady-state mRNA abundance, mRNA stability and protein production. We found widespread regulatory effects on mRNA that were coupled to effects on mRNA stability and protein production. Furthermore, we discovered 87 novel cis-regulatory elements and measured the effects of genetic variation within known and novel 3' UTR motifs. This work shows how massively parallel approaches can improve the functional annotation of noncoding sequences, advance our understanding of cis-regulatory mechanisms and quantify the effects of human genetic variation.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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