bims-agalsp 2023-04-02 papers

Issue of 2023–04–02
three papers selected by
Dongmeng Wang, King’s College

bioRxiv. 2023 Mar 21. pii: 2023.03.17.531557. [Epub ahead of print]

Long-read proteogenomics to connect disease-associated sQTLs to the protein isoform effectors of disease.

Abdullah Abood, Larry D Mesner, Erin D Jeffery, Mayank Murali, Micah Lehe, Jamie Saquing, Charles R Farber, Gloria M Sheynkman.

A major fraction of loci identified by genome-wide association studies (GWASs) lead to alterations in alternative splicing, but interpretation of how such alterations impact proteins is hindered by the technical limitations of short-read RNA-seq, which cannot directly link splicing events to full-length transcript or protein isoforms. Long-read RNA-seq represents a powerful tool to define and quantify transcript isoforms, and recently, infer protein isoform existence. Here we present a novel approach that integrates information from GWAS, splicing QTL (sQTL), and PacBio long-read RNA-seq in a disease-relevant model to infer the effects of sQTLs on the ultimate protein isoform products they encode. We demonstrate the utility of our approach using bone mineral density (BMD) GWAS data. We identified 1,863 sQTLs from the Genotype-Tissue Expression (GTEx) project in 732 protein-coding genes which colocalized with BMD associations (H 4 PP ≥ 0.75). We generated deep coverage PacBio long-read RNA-seq data (N=∼22 million full-length reads) on human osteoblasts, identifying 68,326 protein-coding isoforms, of which 17,375 (25%) were novel. By casting the colocalized sQTLs directly onto protein isoforms, we connected 809 sQTLs to 2,029 protein isoforms from 441 genes expressed in osteoblasts. Using these data, we created one of the first proteome-scale resources defining full-length isoforms impacted by colocalized sQTLs. Overall, we found that 74 sQTLs influenced isoforms likely impacted by nonsense mediated decay (NMD) and 190 that potentially resulted in the expression of new protein isoforms. Finally, we identified colocalizing sQTLs in TPM2 for splice junctions between two mutually exclusive exons, and two different transcript termination sites, making it impossible to interpret without long-read RNA-seq data. siRNA mediated knockdown in osteoblasts showed two TPM2 isoforms with opposing effects on mineralization. We expect our approach to be widely generalizable across diverse clinical traits and accelerate system-scale analyses of protein isoform activities modulated by GWAS loci.

DOI: https://doi.org/10.1101/2023.03.17.531557

Biomolecules. 2023 03 20. pii: 561. [Epub ahead of print]13(3):

Alternative mRNA Splicing and Promising Therapies in Cancer.

James D Fackenthal.

Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and progression. The distribution of alternate mRNA splicing variants in cancer cells is different from their non-cancer counterparts, and cancer cells are more sensitive than non-cancer cells to drugs that target components of the splicing regulatory network. While many of the alternatively spliced mRNAs in cancer cells may represent "noise" from splicing dysregulation, certain recurring splicing variants have been shown to contribute to tumor progression. Some pathogenic splicing disruption events result from mutations in cis-acting splicing regulatory sequences in disease-associated genes, while others may result from shifts in balance among naturally occurring alternate splicing variants among mRNAs that participate in cell cycle progression and the regulation of apoptosis. This review provides examples of cancer-related alternate splicing events resulting from each step of mRNA processing and the promising therapies that may be used to address them.

Keywords: alternative mRNA splicing; cancer; targeted therapies

DOI: https://doi.org/10.3390/biom13030561

Antioxidants (Basel). 2023 Mar 06. pii: 651. [Epub ahead of print]12(3):

Aging Hallmarks and the Role of Oxidative Stress.

Edio Maldonado, Sebastián Morales-Pison, Fabiola Urbina, Aldo Solari.

Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.

Keywords: ROS; aging; mitochondrial dysfunction; oxidative stress

DOI: https://doi.org/10.3390/antiox12030651