Large-scale sequencing efforts have been undertaken to understand the mutational landscape of the coding genome. However, the vast majority of variants occur within non-coding genomic regions. We designed an integrative computational and experimental framework to identify recurrently mutated non-coding regulatory regions that drive tumor progression. Applying this framework to sequencing data from a large prostate cancer patient cohort revealed a large set of candidate drivers. We used (1) in silico analyses, (2) massively parallel reporter assays, and (3) in vivo CRISPR interference screens to systematically validate metastatic castration-resistant prostate cancer (mCRPC) drivers. One identified enhancer region, GH22I030351, acts on a bidirectional promoter to simultaneously modulate expression of the U2-associated splicing factor SF3A1 and chromosomal protein CCDC157. SF3A1 and CCDC157 promote tumor growth in vivo. We nominated a number of transcription factors, notably SOX6, to regulate expression of SF3A1 and CCDC157. Our integrative approach enables the systematic detection of non-coding regulatory regions that drive human cancers.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466230 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2024.114764 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Research progress of non-coding RNA regulating the role of PANoptosis in diabetes mellitus and its complications.
Apoptosis
January 2025
Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Diabetes is a chronic metabolic disease that is endemic worldwide and is characterized by persistent hyperglycemia accompanied by multiple severe complications, including cardiovascular disease, kidney dysfunction, neuropathy, and retinopathy. The pathogenesis of diabetes mellitus and its complications is multifactorial, involving various molecular and cellular pathways. In recent years, research has indicated that mechanisms of cell death play a significant role in the advancement of diabetes and its complications.
View Article and Find Full Text PDFExosomes and non-coding RNAs: bridging the gap in Alzheimer's pathogenesis and therapeutics.
Metab Brain Dis
January 2025
Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, 530000, China.
Alzheimer's disease (AD) is a neurodegenerative disease that primarily affects the elderly population and is the leading cause of dementia. Meanwhile, the vascular hypothesis suggests that vascular damage occurs in the early stages of the disease, leading to neurodegeneration and hindered waste clearance, which in turn triggers a series of events including the accumulation of amyloid plaques and Tau protein tangles. Non-coding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been found to be involved in the regulation of AD.
View Article and Find Full Text PDFCircular RNAs: key players in tumor immune evasion.
Mol Cell Biochem
January 2025
Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Immune responses against tumor antigens play a role in confining tumor growth. In response, cancer cells developed several mechanisms to bypass or defeat these anti-tumor immune responses-collectively referred to as "tumor immune evasion". Recent studies have shown that a group of non-coding RNAs, namely circRNAs affect several aspects of tumor immune evasion through regulation of activity of CD8 + T cells, regulatory T cells, natural killer cells, cytokine-induced killer cells or other immune cells.
View Article and Find Full Text PDFEpigenetics in autosomal dominant polycystic kidney disease.
Biochim Biophys Acta Mol Basis Dis
January 2025
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA. Electronic address:
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage renal disease, contributing substantially to patient morbidity, mortality, and healthcare system strain. Emerging research highlights a pivotal role of epigenetics in ADPKD's pathophysiology, where mechanisms like DNA methylation, histone modifications, and non-coding RNA regulation significantly impact disease onset and progression. These epigenetic factors influence gene expression and regulate key processes involved in cyst formation and expansion, fibrosis, and inflammatory infiltration, thus accelerating ADPKD progression.
View Article and Find Full Text PDFSystematic functional characterization of non-coding regulatory SNPs associated with central obesity.
Am J Hum Genet
January 2025
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China. Electronic address:
Central obesity is associated with higher risk of developing a wide range of diseases independent of overall obesity. Genome-wide association studies (GWASs) have identified more than 300 susceptibility loci associated with central obesity. However, the functional understanding of these loci is limited by the fact that most loci are in non-coding regions.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!