Networks of mRNA Processing and Alternative Splicing Regulation in Health and Disease

Jordan, Peter; Gonçalves, Vânia; Fernandes, Sara; Marques, Tânia Monteiro; Pereira, Marcelo; Gama‐Carvalho, Margarida

doi:10.1007/978-3-030-19966-1_1

Cited by 10 publications

(12 citation statements)

References 203 publications

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“…Studies have demonstrated that RNA processing plays an essential role in determining protein expression levels (Jordan et al, 2019). To determine if male-female cardiac mRNA differences are related to changes in protein abundances, we conducted quantitative mass spectrometry (MS) analyses ( Fig.…”

Section: Cardiac Sex Differences Are Established By Post-transcriptiomentioning

confidence: 99%

Cardiac Sex Differences are Established Prior to Gonad Formation

Shi¹,

Sheng

Dorr³

et al. 2020

Preprint

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Male and female disease states differ in their prevalence, treatment responses, and survival rates. In cardiac disease, women almost uniformly fare far worse than men. Though sex plays a critical role in cardiac disease, the mechanisms underlying sex differences in cardiac homeostasis and disease remain unexplained. Here, in adult and embryonic hearts we reveal sex-specific transcriptomes and proteomes and show that cardiac sex differences are predominately accounted for by post-transcriptional mechanisms. We found differential expression of male-female proteins in the cardiomyocytes. Using a quantitative proteomics-based approach, we characterized differential sex-specific enriched cardiac proteins, protein complexes, and biological sex processes in the context of global genetic diversity of the Collaborative Cross, an established surrogate for human diversity. We also found that sex differences in cardiac protein expression are established by both hormonal and sex chromosomal mechanisms. We have demonstrated the onset of sex-biased protein expression and discovered that sex disparities in heart tissue occur at the earliest stages of heart development at a period that preceeds mammalian gonadal development. Collectively, these findings may explain why congenital heart disease, a leading cause of death whose origin is often developmental, is sex biased. Our results reveal molecular foundations for differences in cardiac tissue that underlie sex disparities in health, disease, and treatment outcomes.

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Section: Cardiac Sex Differences Are Established By Post-transcriptiomentioning

confidence: 99%

Cardiac Sex Differences are Established Prior to Gonad Formation

Shi¹,

Sheng

Dorr³

et al. 2020

Preprint

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“…So far, seven basic types of alternative splicing have been identified, including exon skipping, alternative 5′-splice site, alternative 3′-splice site, mutually exclusive exons, intron retention, alternative promoter, and alternative polyadenylation [ 2 ] ( Figure 1 ). A notable example of alternative splicing is the human gene TTN which encodes muscle protein titin and contains 364 coding-exons and 4039 different splicing events which have been identified by RNA-sequencing [ 3 ]. Most genes generate at least two transcript variants.…”

Section: Introductionmentioning

confidence: 99%

“…The alternative spliced mRNAs are further translated into many protein variants which differ in function and structure. The precision and diversity of alternative splicing events are aided by many significant factors, such as the strength or weakness of splice sites, the concentration and combination of enhancing and silencing splicing factors, chromatin modifications, and RNA secondary architectures [ 3 ]. Since the activity of splicing factors and the spliced variants change the developing process of diseases, they can also serve as experimental indicators or biomarkers for diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Alternative Splicing and Isoforms: From Mechanisms to Diseases

Liu

Fang

2022

Genes

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Alternative splicing of pre-mRNA is a key mechanism for increasing the complexity of proteins in humans, causing a diversity of expression of transcriptomes and proteomes in a tissue-specific manner. Alternative splicing is regulated by a variety of splicing factors. However, the changes and errors of splicing regulation caused by splicing factors are strongly related to many diseases, something which represents one of this study’s main interests. Further understanding of alternative splicing regulation mediated by cellular factors is also a prospective choice to develop specific drugs for targeting the dynamic RNA splicing process. In this review, we firstly concluded the basic principle of alternative splicing. Afterwards, we showed how splicing isoforms affect physiological activities through specific disease examples. Finally, the available treatment methods relative to adjusting splicing activities have been summarized.

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“…Pre-mRNA is synthesized in the nucleus, where it undergoes capping/polyadenylation and splicing, as well as several post-transcriptional modifications. The mRNA is then transported out of the nucleus to the cytoplasm, where it is translated into protein and subsequently degraded [ 1 ]. This whole process involves a highly regulated network of events that are all critical for the cell’s functioning.…”

Section: Introductionmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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Networks of mRNA Processing and Alternative Splicing Regulation in Health and Disease

Cited by 10 publications

References 203 publications

Cardiac Sex Differences are Established Prior to Gonad Formation

Cardiac Sex Differences are Established Prior to Gonad Formation

Alternative Splicing and Isoforms: From Mechanisms to Diseases

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

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