Alternative polyadenylation (APA) is observed in virtually all metazoans and results in mRNA isoforms with different 3’ends. It is routinely...

23Background: Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease 24 characterized by progressive muscle degeneration. The condition is driven by nonsense 25 and missense mutations in the dystrophin gene, but the resulting changes in muscle-26 specific gene expression that take place in dystrophin's absence remain uncharacterized, 27 as they are potentially obscured by the chronic inflammation elicited by muscle damage in 28 humans. C. elegans possess a mild inflammatory response that allows for the 29 characterization of the transcriptome rearrangements affecting disease progression 30 independently of inflammation. 31Results: In effort to better understand these dynamics we have isolated and sequenced 32 body muscle-specific transcriptomes from C. elegans lacking functional dystrophin at 33 distinct stages of disease progression. We have identified two consecutively altered gene 34 networks, which are also disrupted in the dystrophin deficient mdx mouse model. We 35 found an upregulation of genes involved in mitochondrial function early in disease 36 progression, and an upregulation of genes related to muscle fibre repair in later stages. 37 This suggests that dystrophin may have a signaling role early in development, and its 38 absence may activate compensatory mechanisms that counteract muscle degradation 39 caused by loss of dystrophin. We have also developed a temperature-based screening 40 method for synthetic paralysis that can be used to rapidly identify genetic partners of 41 dystrophin. 42 Conclusions: Our results allow for the comprehensive identification of transcriptome 43 rearrangements that potentially serve as independent drivers of disease progression and 44 may in turn allow for the identification of new therapeutic targets for the treatment of DMD. 45 BACKGROUND 46 47Duchenne muscular dystrophy (DMD) is an X-linked, recessive disease caused by 48 out of frame mutations in the dystrophin gene [1]. The dystrophin gene codes for a 49 structural protein found beneath the sarcolemma, where it is anchored both to the 50 dystrophin glycoprotein complex (DGC) and cytoskeletal actin, thus stabilizing the protein 51 complex and the integrity of the cell membrane [2]. In humans, the absence of functional 52 dystrophin results in progressive degeneration of the skeletal and cardiac muscles. The 53 hallmark symptoms of DMD extend beyond muscle degeneration to include respiratory 54 failure, cardiomyopathy, and pseudohypertrophy. The condition remains the most 55 commonly diagnosed type of muscular dystrophy, affecting approximately 1 in 3,500 male 56 births globally. 57 While the role of dystrophin in forming a physical connection between the 58 extracellular matrix (ECM) and cytoskeleton has been well characterized [3], a 59 comprehensive molecular definition of dystrophin's function is not fully understood. 60 Vertebrate models of DMD include the mdx mouse [4] and the golden retriever muscular 61 dystrophy canine [5]. Both models have contributed significantly towar...