bims-agalsp Biomed News
on Ageing and alternative splicing
Issue of 2023–02–26
nine papers selected by
Dongmeng Wang, King’s College
  1. Integrative multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci.
  2. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
  3. Exploring the genetic basis of coronary artery disease using functional genomics.
  4. Network expansion of genetic associations defines a pleiotropy map of human cell biology.
  5. DNA methylation as a powerful tool to investigate the biology and pathology of aging.
  6. Sleep and Memory: The Impact of Sleep Deprivation on Transcription, Translational Control, and Protein Synthesis in the Brain.
  7. The association of physical activity behaviors and patterns with aging acceleration: evidence from the UK Biobank.
  8. Decoupling of mRNA and Protein Expression in Aging Brains Reveals the Age-Dependent Adaptation of Specific Gene Subsets.
  9. Alzheimer's Disease-Associated Alternative Splicing of CD33 Is Regulated by the HNRNPA Family Proteins.
  1. medRxiv. 2023 Feb 14. pii: 2023.02.09.23285622. [Epub ahead of print]
    Integrative multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci.
    Chani J Hodonsky, Adam W Turner, Mohammad Daud Khan, Nelson B Barrientos, Ruben Methorst, Lijiang Ma, Nicolas G Lopez, Jose Verdezoto Mosquera, Gaëlle Auguste, Emily Farber, Wei Feng Ma, Doris Wong, Suna Onengut-Gumuscu, Maryam Kavousi, Patricia A Peyser, Sander W van der Laan, Nicholas J Leeper, Jason C Kovacic, Johan L M Björkegren, Clint L Miller.
      Genome-wide association studies (GWAS) have identified hundreds of genetic risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWAS and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotype information to identify quantitative trait loci (QTL) for gene expression and splicing in coronary arteries obtained from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary arteries and 19% exhibited cell-type-specific expression. Colocalization analysis with GWAS identified subgroups of eGenes unique to CAD and blood pressure. Fine-mapping highlighted additional eGenes of interest, including TBX20 and IL5 . Splicing (s)QTLs for 1,690 genes were also identified, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing events to accurately identify disease-relevant gene expression. Our work provides the first human coronary artery eQTL resource from a patient sample and exemplifies the necessity of diverse study populations and multi-omic approaches to characterize gene regulation in critical disease processes.
    Study Design Overview:
    DOI:  https://doi.org/10.1101/2023.02.09.23285622
  2. bioRxiv. 2023 Feb 15. pii: 2023.02.15.528714. [Epub ahead of print]
    Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
    James R Occean, Na Yang, Yan Sun, Marshall S Dawkins, Rachel Munk, Cedric Belair, Showkat Dar, Carlos Anerillas, Lin Wang, Changyou Shi, Christopher Dunn, Michel Bernier, Nathan L Price, Julie S Kim, Chang-Yi Cui, Jinshui Fan, Moitrayee Bhattacharyya, Supriyo De, Manolis Maragkakis, Rafael deCabo, Simone Sidoli, Payel Sen.
      DNA hydroxymethylation (5hmC) is the most abundant oxidative derivative of DNA methylation (5mC) and is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in many age-related diseases, the functional role of the modification in aging remains largely unknown. Here, we report that 5hmC is stably enriched in multiple aged organs. Using the liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and thereby restricts the magnitude of gene expression changes during aging. Mechanistically, we found that 5hmC decreases binding affinity of splicing factors compared to unmodified cytosine and 5mC, and is correlated with age-related alternative splicing events, suggesting RNA splicing as a potential mediator of 5hmC’s transcriptionally restrictive function. Furthermore, we show that various age-related contexts, such as prolonged quiescence and senescence, are partially responsible for driving the accumulation of 5hmC with age. We provide evidence that this age-related function is conserved in mouse and human tissues, and further show that the modification is altered by regimens known to modulate lifespan. Our findings reveal that 5hmC is a regulator of tissue-specific function and may play a role in regulating longevity.
    DOI:  https://doi.org/10.1101/2023.02.15.528714
  3. Atherosclerosis. 2023 Feb 02. pii: S0021-9150(23)00046-1. [Epub ahead of print]
    Exploring the genetic basis of coronary artery disease using functional genomics.
    Maykel López Rodríguez, Uma Thanigai Arasu, Minna U Kaikkonen.
      Genome-wide Association Studies (GWAS) have identified more than 300 loci associated with coronary artery disease (CAD), defining the genetic risk map of the disease. However, the translation of the association signals into biological-pathophysiological mechanisms constitute a major challenge. Through a group of examples of studies focused on CAD, we discuss the rationale, basic principles and outcomes of the main methodologies implemented to prioritize and characterize causal variants and their target genes. Additionally, we highlight the strategies as well as the current methods that integrate association and functional genomics data to dissect the cellular specificity underlying the complexity of disease mechanisms. Despite the limitations of existing approaches, the increasing knowledge generated through functional studies helps interpret GWAS maps and opens novel avenues for the clinical usability of association data.
    Keywords:  Atherosclerosis; Coronary artery disease; Coronary heart disease; Functional genomics; GWAS; Genetics
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2023.01.019
  4. Nat Genet. 2023 Feb 23.
    Network expansion of genetic associations defines a pleiotropy map of human cell biology.
    Inigo Barrio-Hernandez, Jeremy Schwartzentruber, Anjali Shrivastava, Noemi Del-Toro, Asier Gonzalez, Qian Zhang, Edward Mountjoy, Daniel Suveges, David Ochoa, Maya Ghoussaini, Glyn Bradley, Henning Hermjakob, Sandra Orchard, Ian Dunham, Carl A Anderson, Pablo Porras, Pedro Beltrao.
      Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support.
    DOI:  https://doi.org/10.1038/s41588-023-01327-9
  5. Epigenomics. 2023 Feb 21.
    DNA methylation as a powerful tool to investigate the biology and pathology of aging.
    Fabio Coppedè.
      
    Keywords:  DNA methylation age; DNA methylation clocks; aging; biological age; biology of aging; epigenetic clocks; human disease; pathology of aging; risk predictors; sperm cell methylation
    DOI:  https://doi.org/10.2217/epi-2023-0011
  6. J Neurochem. 2023 Feb 18.
    Sleep and Memory: The Impact of Sleep Deprivation on Transcription, Translational Control, and Protein Synthesis in the Brain.
    Lisa C Lyons, Yann Vanrobaeys, Ted Abel.
      In countries around the world, sleep deprivation represents a widespread problem affecting school age children, teenagers and adults. Acute sleep deprivation and more chronic sleep restriction adversely affect individual health, impairing memory and cognitive performance as well as increasing the risk and progression of numerous diseases. In mammals, the hippocampus and hippocampus-dependent memory is vulnerable to the effects of acute sleep deprivation. Sleep deprivation induces changes in molecular signaling, gene expression and may cause changes in dendritic structure in neurons. Genome wide studies have shown that acute sleep deprivation alters gene transcription, although the pool of genes affected varies between brain regions. More recently, advances in research have drawn attention to differences in gene regulation between the level of the transcriptome compared with the pool of mRNA associated with ribosomes for protein translation following sleep deprivation. Thus, in addition to transcriptional changes, sleep deprivation also affects downstream processes to alter protein translation. In this review, we focus on the multiple levels through which acute sleep deprivation impacts gene regulation, highlighting potential post-transcriptional and translational processes that may be affected by sleep deprivation. Understanding the multiple levels of gene regulation impacted by sleep deprivation is essential for future development of therapeutics that may mitigate the effects of sleep loss.
    Keywords:  gene expression; hippocampus; memory; ribosome; sleep deprivation; translation
    DOI:  https://doi.org/10.1111/jnc.15787
  7. J Gerontol A Biol Sci Med Sci. 2023 Feb 23. pii: glad064. [Epub ahead of print]
    The association of physical activity behaviors and patterns with aging acceleration: evidence from the UK Biobank.
    Jianwei Zhu, Yao Yang, Yu Zeng, Xin Han, Wenwen Chen, Yao Hu, Yuanyuan Qu, Huazhen Yang, Unnur A Valdimarsdóttir, Fang Fang, Huan Song.
      Prior evidence suggests that physical activity may reduce the risk of multiple diseases and mortality. However, whether and how physical activity affects the aging process remains largely unexplored. We included 284,479 UK Biobank participants and computed leukocyte telomere length (LTL) deviation (i.e., the difference between genetically determined and observed LTL) and biological age acceleration (BAA, defined as the discrepancy between the phenotypic age of a person and the average phenotypic age in the cohort of individuals with the same age and sex) as the indexes for aging acceleration. Linear and logistic models were used to estimate the associations of self-reported physical activity items and patterns (identified by principal component analysis), as well as accelerometer-assessed physical activity, with aging acceleration. Analyses of physical activity patterns indicated, a higher level of adherence to activity patterns predominated by strenuous sports, other exercises, walking for pleasure, heavy and light housework, and public transportation use was associated with a lower risk of aging acceleration, whereas a higher level of adherence to patterns predominated by job-related activities was associated with a higher risk of aging acceleration. Analysis among 62,418 participants with accelerometer-measured physical activity corroborated these results. Physical activity, such as strenuous sports and other exercises at leisure time and use of public transportation, was associated with a reduced biological aging. Besides highlighting the importance of engaging in physical activity for healthy aging, our results provide further evidence for the beneficial effect of physical activity on the telomere attrition process.
    Keywords:  biological aging; leukocyte telomere length; physical activity; polygenic risk score; principal component analysis
    DOI:  https://doi.org/10.1093/gerona/glad064
  8. Cells. 2023 Feb 14. pii: 615. [Epub ahead of print]12(4):
    Decoupling of mRNA and Protein Expression in Aging Brains Reveals the Age-Dependent Adaptation of Specific Gene Subsets.
    Inès Khatir, Marie A Brunet, Anna Meller, Florent Amiot, Tushar Patel, Xavier Lapointe, Jessica Avila Lopez, Noé Guilloy, Anne Castonguay, Mohammed Amir Husain, Joannie St Germain, François-Michel Boisvert, Mélanie Plourde, Xavier Roucou, Benoit Laurent.
      During aging, changes in gene expression are associated with a decline in physical and cognitive abilities. Here, we investigate the connection between changes in mRNA and protein expression in the brain by comparing the transcriptome and proteome of the mouse cortex during aging. Our transcriptomic analysis revealed that aging mainly triggers gene activation in the cortex. We showed that an increase in mRNA expression correlates with protein expression, specifically in the anterior cingulate cortex, where we also observed an increase in cortical thickness during aging. Genes exhibiting an aging-dependent increase of mRNA and protein levels are involved in sensory perception and immune functions. Our proteomic analysis also identified changes in protein abundance in the aging cortex and highlighted a subset of proteins that were differentially enriched but exhibited stable mRNA levels during aging, implying the contribution of aging-related post- transcriptional and post-translational mechanisms. These specific genes were associated with general biological processes such as translation, ribosome assembly and protein degradation, and also important brain functions related to neuroplasticity. By decoupling mRNA and protein expression, we have thus characterized distinct subsets of genes that differentially adjust to cellular aging in the cerebral cortex.
    Keywords:  aging; brain; cortex; mRNA; protein; proteome; transcriptome
    DOI:  https://doi.org/10.3390/cells12040615
  9. Cells. 2023 Feb 13. pii: 602. [Epub ahead of print]12(4):
    Alzheimer's Disease-Associated Alternative Splicing of CD33 Is Regulated by the HNRNPA Family Proteins.
    Riho Komuro, Yuka Honda, Motoaki Yanaizu, Masami Nagahama, Yoshihiro Kino.
      Genetic variations of CD33 have been implicated as a susceptibility factor of Alzheimer's disease (AD). A polymorphism on exon 2 of CD33, rs12459419, affects the alternative splicing of this exon. The minor allele is associated with a reduced risk of AD and promotes the skipping of exon 2 to produce a shorter CD33 isoform lacking the extracellular ligand-binding domain, leading to decreased suppressive signaling on microglial activity. Therefore, factors that regulate the splicing of exon 2 may alter the disease-associated properties of CD33. Herein, we sought to identify the regulatory proteins of CD33 splicing. Using a panel of RNA-binding proteins and a human CD33 minigene, we found that exon 2 skipping of CD33 was promoted by HNRNPA1. Although the knockdown of HNRNPA1 alone did not reduce exon 2 skipping, simultaneous knockdown of HNRNPA1 together with that of HNRNPA2B1 and HNRNPA3 promoted exon 2 inclusion, suggesting functional redundancy among HNRNPA proteins. Similar redundant regulation by HNRNPA proteins was observed in endogenous CD33 of THP-1 and human microglia-like cells. Although mouse Cd33 showed a unique splicing pattern of exon 2, we confirmed that HNRNPA1 promoted the skipping of this exon. Collectively, our results revealed novel regulatory relationships between CD33 and HNRNPA proteins.
    Keywords:  Alzheimer’s disease; CD33; HNRNPA1; alternative splicing
    DOI:  https://doi.org/10.3390/cells12040602
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