bims-agalsp 2023-03-26 papers

Issue of 2023–03–26
four papers selected by
Dongmeng Wang, King’s College

Cancer Res. 2023 Mar 20. pii: CAN-22-3184. [Epub ahead of print]

Genome-wide splicing QTL analysis identifies causal risk variants for non-small cell lung cancer.

Meng Jin, Bo Liu, Can Chen, Yongbiao Huang, Huixian Zhang, Bingliang Chen, Guoda Song, Dong Zhao, Limin Duan, Wei Liu, Haizhen Yang, Fang Yue, Peijun Liu, Xianglin Yuan, Qian Chu, Jianbo Tian, Ke Hu.

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies(GWAS) have been linked to expression quantitative trait loci(eQTLs) in previous studies,further work is needed to better elucidate the relationship to other genetic regulatory mechanisms,such as splicing QTLs(sQTLs). Here,we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer(NSCLC) samples from The Cancer Genome Atlas(TCGA).The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions,genetic regulatory elements,RNA binding protein(RBP) binding sites, and known NSCLC risk loci. Additionally, target genes affected by sQTLs(sGenes) were involved in multiple processes in cancer,including cell growth,apoptosis,metabolism,immune infiltration,and drug responses,and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform(GSTO2-V1) and lower expression of the truncated GSTO2 isoform(GSTO2-V2),which was induced by RBP quaking(QKI). Mechanistically,compared with GSTO2-V1,GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall,this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3184

EMBO J. 2023 Mar 21. e111762

Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.

Ye Xiao, Guang-Ping Cai, Xu Feng, Yu-Jue Li, Wan-Hui Guo, Qi Guo, Yan Huang, Tian Su, Chang-Jun Li, Xiang-Hang Luo, Yong-Jun Zheng, Mi Yang.

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.

Keywords: Y-box binding protein 1; aging; alternative splicing; bone marrow stromal cells

DOI: https://doi.org/10.15252/embj.2022111762

Genome Biol. 2023 Mar 22. 24(1): 53

Evidence for the role of transcription factors in the co-transcriptional regulation of intron retention.

Fahad Ullah, Saira Jabeen, Maayan Salton, Anireddy S N Reddy, Asa Ben-Hur.

BACKGROUND: Alternative splicing is a widespread regulatory phenomenon that enables a single gene to produce multiple transcripts. Among the different types of alternative splicing, intron retention is one of the least explored despite its high prevalence in both plants and animals. The recent discovery that the majority of splicing is co-transcriptional has led to the finding that chromatin state affects alternative splicing. Therefore, it is plausible that transcription factors can regulate splicing outcomes.
RESULTS: We provide evidence for the hypothesis that transcription factors are involved in the regulation of intron retention by studying regions of open chromatin in retained and excised introns. Using deep learning models designed to distinguish between regions of open chromatin in retained introns and non-retained introns, we identified motifs enriched in IR events with significant hits to known human transcription factors. Our model predicts that the majority of transcription factors that affect intron retention come from the zinc finger family. We demonstrate the validity of these predictions using ChIP-seq data for multiple zinc finger transcription factors and find strong over-representation for their peaks in intron retention events.
CONCLUSIONS: This work opens up opportunities for further studies that elucidate the mechanisms by which transcription factors affect intron retention and other forms of splicing.
AVAILABILITY: Source code available at https://github.com/fahadahaf/chromir.

Keywords: Alternative splicing; Deep learning; Intron retention

DOI: https://doi.org/10.1186/s13059-023-02885-1

Nat Commun. 2023 Mar 22. 14(1): 1589

Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer.

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53, CDKN2A, and B2M, and other genes.

DOI: https://doi.org/10.1038/s41467-023-37266-6