bims-agalsp 2023-03-19 papers

Issue of 2023–03–19
five papers selected by
Dongmeng Wang, King’s College

HGG Adv. 2023 Apr 13. 4(2): 100185

Splicing annotation of endometrial cancer GWAS risk loci reveals potentially causal variants and supports a role for NF1 and SKAP1 as susceptibility genes.

Daffodil M Canson, Tracy A O'Mara, Amanda B Spurdle, Dylan M Glubb.

Alternative splicing contributes to cancer development. Indeed, splicing analysis of cancer genome-wide association study (GWAS) risk variants has revealed likely causal variants. To systematically assess GWAS variants for splicing effects, we developed a prioritization workflow using a combination of splicing prediction tools, alternative transcript isoforms, and splicing quantitative trait locus (sQTL) annotations. Application of this workflow to candidate causal variants from 16 endometrial cancer GWAS risk loci highlighted single-nucleotide polymorphisms (SNPs) that were predicted to upregulate alternative transcripts. For two variants, sQTL data supported the predicted impact on splicing. At the 17q11.2 locus, the protective allele for rs7502834 was associated with increased splicing of an exon in a NF1 alternative transcript encoding a truncated protein in adipose tissue and is consistent with an endometrial cancer transcriptome-wide association study (TWAS) finding in adipose tissue. Notably, NF1 haploinsufficiency is protective for obesity, a well-established risk factor for endometrial cancer. At the 17q21.32 locus, the rs2278868 risk allele was predicted to upregulate a SKAP1 transcript that is subject to nonsense-mediated decay, concordant with a corresponding sQTL in lymphocytes. This is consistent with a TWAS finding that indicates decreased SKAP1 expression in blood increases endometrial cancer risk. As SKAP1 is involved in T cell immune responses, decreased SKAP1 expression may impact endometrial tumor immunosurveillance. In summary, our analysis has identified potentially causal endometrial cancer GWAS risk variants with plausible biological mechanisms and provides a splicing annotation workflow to aid interpretation of other GWAS datasets.

Keywords: GWAS; NF1; SKAP1; SpliceAI-10k calculator; endometrial cancer; sQTL; spliceogenic; splicing

DOI: https://doi.org/10.1016/j.xhgg.2023.100185

PLoS Comput Biol. 2023 Mar 17. 19(3): e1010939

PCB: A pseudotemporal causality-based Bayesian approach to identify EMT-associated regulatory relationships of AS events and RBPs during breast cancer progression.

Liangjie Sun, Yushan Qiu, Wai-Ki Ching, Pu Zhao, Quan Zou.

During breast cancer metastasis, the developmental process epithelial-mesenchymal (EM) transition is abnormally activated. Transcriptional regulatory networks controlling EM transition are well-studied; however, alternative RNA splicing also plays a critical regulatory role during this process. Alternative splicing was proved to control the EM transition process, and RNA-binding proteins were determined to regulate alternative splicing. A comprehensive understanding of alternative splicing and the RNA-binding proteins that regulate it during EM transition and their dynamic impact on breast cancer remains largely unknown. To accurately study the dynamic regulatory relationships, time-series data of the EM transition process are essential. However, only cross-sectional data of epithelial and mesenchymal specimens are available. Therefore, we developed a pseudotemporal causality-based Bayesian (PCB) approach to infer the dynamic regulatory relationships between alternative splicing events and RNA-binding proteins. Our study sheds light on facilitating the regulatory network-based approach to identify key RNA-binding proteins or target alternative splicing events for the diagnosis or treatment of cancers. The data and code for PCB are available at: http://hkumath.hku.hk/~wkc/PCB(data+code).zip.

DOI: https://doi.org/10.1371/journal.pcbi.1010939

DNA Repair (Amst). 2023 Mar 09. pii: S1568-7864(23)00037-X. [Epub ahead of print]125 103483

DNA damage-induced stalling of transcription drives aging through gene expression imbalance.

Austin A Sims, Aditi U Gurkar.

Age-related changes in gene expression have long been examined to understand the biology of aging. The hallmarks of aging are biological processes known to be associated with aging, but whether there is a unifying driver of these attributes, is not well understood. With the advent of technology over the last few years, it is quite clear that aging leads to global decline in transcription. In this Perspective, we highlight a new study in Nature Genetics that aimed to determine why global transcription rate reduces with age and how this phenomenon is the driver that interconnects multiple hallmarks of aging. This study recognizes that age-related accumulation of DNA damage, particularly transcription-blocking lesions, stalls RNA polymerase. This phenomenon affects longer genes leading to a gradual loss of transcription and skewing the transcriptome. In order to design a successful aging intervention, future work will be needed to test how some promising therapies in pre-clinical trials target affect transcriptional rate.

Keywords: Aging; DNA damage; Gene expression; Transcription loss

DOI: https://doi.org/10.1016/j.dnarep.2023.103483

Ageing Res Rev. 2023 Mar 15. pii: S1568-1637(23)00071-5. [Epub ahead of print]87 101912

Revisiting adipose thermogenesis for delaying aging and age-related diseases: Opportunities and challenges.

Stefano Tarantini, Madhan Subramanian, Joshua T Butcher, Andriy Yabluchanskiy, Xinna Li, Richard A Miller, Priya Balasubramanian.

Adipose tissue undergoes significant changes in structure, composition, and function with age including altered adipokine secretion, decreased adipogenesis, altered immune cell profile and increased inflammation. Considering the role of adipose tissue in whole-body energy homeostasis, age-related dysfunction in adipose metabolism could potentially contribute to an increased risk for metabolic diseases and accelerate the onset of other age-related diseases. Increasing cellular energy expenditure in adipose tissue, also referred to as thermogenesis, has emerged as a promising strategy to improve adipose metabolism and treat obesity-related metabolic disorders. However, translating this strategy to the aged population comes with several challenges such as decreased thermogenic response and the paucity of safe pharmacological agents to activate thermogenesis. This mini-review aims to discuss the current body of knowledge on aging and thermogenesis and highlight the unexplored opportunities (cellular mechanisms and secreted factors) to target thermogenic mechanisms for delaying aging and age-related diseases. Finally, we also discuss the emerging role of thermogenic adipocytes in healthspan and lifespan extension.

Keywords: Adipose metabolism; Aging; Beta-3 adrenergic agonists; Futile metabolic cycling; Healthspan; Thermogenesis; Uncoupling protein 1

DOI: https://doi.org/10.1016/j.arr.2023.101912

Front Pharmacol. 2023 ;14 1137154

Aberrant splicing in human cancer: An RNA structural code point of view.

Maria Apostolidi, Vassiliki Stamatopoulou.

Alternative splicing represents an essential process that occurs widely in eukaryotes. In humans, most genes undergo alternative splicing to ensure transcriptome and proteome diversity reflecting their functional complexity. Over the last decade, aberrantly spliced transcripts due to mutations in cis- or trans-acting splicing regulators have been tightly associated with cancer development, largely drawing scientific attention. Although a plethora of single proteins, ribonucleoproteins, complexed RNAs, and short RNA sequences have emerged as nodal contributors to the splicing cascade, the role of RNA secondary structures in warranting splicing fidelity has been underestimated. Recent studies have leveraged the establishment of novel high-throughput methodologies and bioinformatic tools to shed light on an additional layer of splicing regulation in the context of RNA structural elements. This short review focuses on the most recent available data on splicing mechanism regulation on the basis of RNA secondary structure, emphasizing the importance of the complex RNA G-quadruplex structures (rG4s), and other specific RNA motifs identified as splicing silencers or enhancers. Moreover, it intends to provide knowledge on newly established techniques that allow the identification of RNA structural elements and highlight the potential to develop new RNA-oriented therapeutic strategies against cancer.

Keywords: RNA G-quadruplexes; RNA motifs; RNA structural code; aberrant splicing; cancer; pre-mRNA processing; transcriptome diversity

DOI: https://doi.org/10.3389/fphar.2023.1137154