Steber, H. | Search bioRxiv

bioRxiv2019

The C. elegans 3’UTRome V2: an updated genomic resource to study 3’UTR biology

3-Untranslated Regions (3-UTRs) of mRNAs emerged as central regulators of cellular function as they contain important but poorly-characterized cis-regulatory elements targeted by a multitude of regulatory factors. The model nematode C. elegans is ideal to study these interactions since it possesses a well-defined 3-UTRome. In order to improve its annotation, we have used a genomics approach to download raw transcriptome data for 1,088 transcriptome datasets corresponding to the entire collection of C. elegans trancriptomes from 2015 to 2018 from the Sequence Read Archive at the NCBI. We then extracted and mapped high-quality 3-UTR data at ultra-deep coverage. Here we describe and release to the community the updated version of the worm 3-UTRome, which we named 3-UTRome v2. This resource contains high-quality 3-UTR data mapped at single base ultra-resolution for 23,084 3-UTR isoform variants corresponding to 14,788 protein-coding genes and is updated to the latest release of WormBase. We used this dataset to study and probe principles of mRNA cleavage and polyadenylation in C. elegans. The worm 3-UTRome v2 represents the most comprehensive and high-resolution 3-UTR dataset available in C. elegans and provides a novel resource to investigate the mRNA cleavage and polyadenylation reaction, 3-UTR biology and miRNA targeting in a living organism.

genomics↗

bioRxiv2019

Consecutive signaling pathways are activated in progression of Duchenne muscular dystrophy in C. elegans

BackgroundDuchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, but the resulting changes in muscle-specific gene expression that take place in dystrophins absence remain uncharacterized, as they are potentially obscured by the chronic inflammation elicited by muscle damage in humans. C. elegans possess a mild inflammatory response that allows for the characterization of the transcriptome rearrangements affecting disease progression independently of inflammation. ResultsIn effort to better understand these dynamics we have isolated and sequenced body muscle-specific transcriptomes from C. elegans lacking functional dystrophin at distinct stages of disease progression. We have identified two consecutively altered gene networks, which are also disrupted in the dystrophin deficient mdx mouse model. We found an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle fibre repair in later stages. This suggests that dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin. ConclusionsOur results allow for the comprehensive identification of transcriptome rearrangements that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD. One Sentence SummaryA tissue specific transcriptome analysis of dystrophin deficient muscle in C. elegans reveals that dystrophin has distinct, dynamic signaling roles in early and late stage progression of Duchenne muscular dystrophy.

genetics↗