Biology subjects

Sun, P.

Publications and source records attributed to Sun, P..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

A TARGETED COMBINATION THERAPY ACHIEVES EFFECTIVE PANCREATIC CANCER REGRESSION AND PREVENTS TUMOR RESISTANCE

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Recent studies using RAS(ON) inhibitors as single agents have opened the door to more efficacious therapies. Here, we demonstrate that genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signaling pathways leads to complete and permanent disappearance of orthotopic PDACs induced by KRAS/TP53 mutations. Likewise, a combination of RAS(ON) (RMC-6236/daraxonrasib), EGFR family (afatinib) and STAT3 (SD36) selective inhibitors/degraders induced the effective regression of these orthotopic tumors with no evidence of tumor resistance for over 200 days post-treatment. This combination therapy also led to significant regression of genetically engineered mouse tumors as well patient-derived tumor xenografts (PDX) in the absence of tumor relapses. Finally, this combination therapy was well tolerated by the animals. These results should guide the development of clinical trials that could benefit PDAC patients.

cancer biology↗

bioRxiv2025

Deciphering complex interactions between LTR retrotransposons and three Papaver species using LTR_Stream

Long terminal repeat retrotransposons (LTR-RTs), a major type of class I transposable elements (TEs), are the most abundant repeat element in plants. The study of the interactions between LTR-RTs and the host genome relies on high-resolution characterization of LTR-RTs. However, for non-model species, this remains a challenge. To address this, we developed LTR_Stream for sub-lineage clustering of LTR-RTs in specific or closely related species, providing higher precision than current database-based lineage-level clustering. Using LTR_Stream, we analyzed Retand LTR-RTs in three Papaver species. Our findings show that high-resolution clustering reveals complex interactions between LTR-RTs and the host genome. For instance, we found autonomous Retand elements could spread among the ancestors of different subgenomes, like retroviruses pandemics, enriching genetic diversity. Additionally, we identified that specific truncated fragments containing transcription factors motifs such as TCP and bZIP may contribute to generation of novel TAD-like boundaries. Notably, our pre- and post-allopolyploidization comparisons show that these effects diminished after allopolyploidization, suggesting that allopolyploidization may be one of the mechanisms by which Papaver species cope with LTR-RTs. We demonstrated the potential application of LTR_Stream and provided a reference case for studying the interactions between LTR-RTs and the host genome in non-model plant species.

bioinformatics↗

bioRxiv2025

Two CENH3 paralogs in the green alga Chlamydomonas reinhardtii have a redundantly essential function and associate with ZeppL-LINE1 elements

Centromeres in eukaryotes are defined by the presence of histone H3 variant CENP-A/CENH3. Chlamydomonas encodes two predicted CENH3 paralogs, CENH3.1 and CENH3.2, that have not been previously characterized. We generated peptide antibodies to unique N-terminal epitopes for each of the two predicted Chlamydomonas CENH3 paralogs as well as an antibody against a shared CENH3 epitope. All three CENH3 antibodies recognized proteins of the expected size on immunoblots and had punctuated nuclear immunofluorescence staining patterns. These results are consistent with both paralogs being expressed and localized to centromeres. CRISPR-Cas9 mediated insertional mutagenesis was used to generate predicted null mutations in either CENH3.1 or CENH3.2. Single mutants were viable but cenh3.1 cenh3.2 double mutants were not recovered, confirming that the function of CENH3 is essential. We sequenced and assembled two chromosome-scale Chlamydomonas genomes from strains CC-400 and UL-1690 (a derivative of CC-1690) with complete centromere sequences for 17/17 and 14/17 chromosomes respectively, enabling us to compare centromere evolution across four isolates with near complete assemblies. These data revealed significant changes across isolates between homologous centromeres including mobility and degeneration of ZeppL-LINE1 (ZeppL) transposons that comprise the major centromere repeat sequence in Chlamydomonas. We used Cleavage Under Targets and Tagmentation (CUT&Tag) to purify and map CENH3-bound genomic sequences and found enrichment of CENH3-binding almost exclusively at predicted centromere regions. An interesting exception was chromosome 2 in UL-1690, which had enrichment at its genetically mapped centromere repeat region as well as a second, distal location, centered around a single recently acquired ZeppL insertion. The CENH3-bound regions of the 17 Chlamydomonas centromeres ranged from 63.5kb (average lower estimate) to 175kb (average upper estimate). The relatively small size of its centromeres suggest that Chlamydomonas may be a useful organism for testing and deploying artificial chromosome technologies. Significance statementHistone H3 variant CENP-A/CENH3 is a conserved centromere protein in eukaryotes but has not been well-characterized in green algae. Our data establish the function of CENH3 at Chlamydomonas centromeres and identify an unexpected strain-specific neocentromere candidate region in chromosome 2 likely caused by a single ZeppL-LINE1 insertion into a genic region that is distal to the native chromosome 2 centromere.

genetics↗

bioRxiv2024

Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multicompartmental alterations in gene expression and signaling cross-talk

Vulvar diseases are a critical yet often neglected area of womens health, profoundly affecting patients quality of life and frequently resulting in long-term physical and psychological challenges. Lichen sclerosus (LS) is a chronic inflammatory skin disorder that predominantly affects the vulva, leading to severe itching, pain, scarring, and an increased risk of malignancy. Despite its profound impact on affected individuals, the molecular pathogenesis of vulvar LS (VLS) is not well understood, hindering the development of FDA-approved therapies. Here, we utilize single-cell and spatial transcriptomics to analyze lesional and non-lesional skin from VLS patients, as well as healthy control vulvar skin. Our findings demonstrate histologic, cellular, and molecular heterogeneities within VLS, yet highlight unifying molecular changes across keratinocytes, fibroblasts, immune cells, and melanocytes in lesional skin. They reveal cellular stress and damage in fibroblasts and keratinocytes, enhanced T cell activation and cytotoxicity, aberrant cell-cell signaling, and increased activation of the IFN, JAK/STAT, and p53 pathways in specific cell types. Using both monolayer and organotypic culture models, we also demonstrate that knockdown of select genes, which are downregulated in VLS lesional keratinocytes, partially recapitulates VLS-like stress-associated changes. Collectively, these data provide novel insights into the pathogenesis of VLS, identifying potential biomarkers and therapeutic targets for future research.

genomics↗

bioRxiv2024

A biodegradable and restorative peripheral neural interface for the interrogation of neuropathic injuries

Monitoring the early-stage healing of severe traumatic nerve injuries is essential to gather physiological and pathological information for timely interventions and optimal clinical outcomes. While implantable peripheral nerve interfaces provide direct access to nerve fibers for precise interrogation and modulation, conventional non-degradable designs pose limited utilization in nerve injury rehabilitation. Here, we introduce a biodegradable and restorative neural interface for wireless real-time tracking and recovery of long-gap nerve injuries. Leveraging machine learning techniques, this electronic platform deciphers nerve recovery status and identifies traumatic neuroma formation at the early phase, enabling timely intervention and significantly improved therapeutic outcomes. The biodegradable nature of the device eliminates the need for retrieval procedures, reducing infection risks and secondary tissue damage. This research sheds light on bioresorbable multifunctional peripheral nerve interfaces for probing neuropathic injuries, offering vital information for early diagnosis and therapeutic intervention.

bioengineering↗

bioRxiv2024

Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions

The class I PI3K-AKT signaling pathway is the master regulator of cell survival, growth, and proliferation, and among the most frequently mutated pathways in cancer. However, where and how the PI3K-AKT signaling is spatially activated and organized in mammalian cells remain poorly understood. Here, we identified focal adhesions (FAs) as the subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in mammalian cells. We found that class IA PI3Ks are preferentially and dynamically recruited to FAs for activation, resulting in localized production of the critical signaling lipid PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT molecules are dynamically recruited around FAs for activation. Mechanistically, the spatial recruitment/activation of PI3K-PI(3,4,5)P3-AKT cascade are regulated by the activated FAK. Furthermore, combined inhibition of class I PI3K and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.

cell biology↗

bioRxiv2024

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

microbiology↗

bioRxiv2024

The cornerstone of early diagnosis and immunotherapy of prostate cancer:screening characteristic genes

BackgroundProstate cancer (PCA) has become a common malignant tumor globally, posing a substantial risk to the health of middle-aged and elderly men. However, there is still a lack of effective strategies for early detection and treatment of prostate cancer. The introduction of gene therapy in recent years has shown promise as a potential approach for cancer diagnosis and treatment. Methodology & Theoretical OrientationThe training set data GSE45016, GSE46602, and GSE69223 from the Gene Expression Omnibus (GEO) dataset, along with validation training set data GSE17951, were utilized. Differentially expressed genes (DEGs) between normal individuals and tumor patients were identified by combining the training set data. Subsequent analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted on the DEGs. WGCNA analysis was then performed on the gene expression matrix to identify module genes highly correlated with PCA, followed by the application of the LASSO algorithm to obtain PCA candidate genes. The candidate genes were validated using the area under the receiver operating characteristic (ROC) curve (AUC) to determine key feature genes. Finally, the relationship between key characteristic genes and immune cells was explored. FindingsA total of 54 DEGs were identified, with 26 down-regulated genes and 28 up-regulated genes. The GO function analysis revealed enrichment in processes such as establishment of protein localization to membrane and protein targeting to membrane. KEGG analysis showed enrichment in pathways like eutrophil degranulation, neutrophil activation involved in immune response, and regulation of cell morphogenesis. GSEA analysis highlighted enrichment in pathways like CTRL_VS_ACT_IL4 AND ANTI_IL12_12H_CD4_TCELL_DN. Through WGCNA and LASSO regression analysis, key characteristic genes MARCKSL1, TMTC4, and TTLL12 were identified, with AUC values greater than 0.8 in both the training and validation sets, and were found to be closely associated with immune cell infiltration. Conclusion & SignificanceMARCKSL1, TMTC4, and TTLL12 emerge as crucial genes in the process of PCA, showing significant relevance to immune cell infiltration.this study offers valuable clinical insights into the diagnosis and treatment of prostate cancer through the identification of specific genes associated with the disease.

genomics↗

bioRxiv2024

AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis

Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we report OVOL1/Ovol1 as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, and Ovol1 deletion in keratinocytes hampers AhRs barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1s direct downstream targets genome-wide, and provide in vivo evidence for Id1s critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal {gamma}{delta}T cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.

molecular biology↗

bioRxiv2023

NASTRA: Innovative Short Tandem Repeat Analysis through Cluster-Based Structure-Aware Algorithm in Nanopore Sequencing Data

Forensic short-tandem repeats (STR) genetic markers are multi-allelic and widely utilized for individual identification, kinship testing, and cell-line authentication. Nanopore sequencing, known for its portability, is emerging as a promising approach for STR typing, facilitating real-time and in-field testing. However, its efficacy is often hampered by sequencing noise. Previous methods rely on alignment-based genotyping, necessitating known alleles, which limits their applicability to unknown alleles. Here, we introduced NASTRA, an innovative allele reference-free tool for precise germline analysis of STR genetic markers. NASTRA incorporates a recursive algorithm to infer repeat structures of allele sequences using only known repeat motifs. Our tests, conducted on 80 individual samples and 8 DNA standards, have demonstrated NASTRAs exceptional 100% accuracy in genotyping nearly all diploid STRs across various multiplex kits and flow cells. It surpasses alignment-based methods in accuracy and speed. In a paternity testing case study, NASTRA accurately identified three relationships among six individuals within an 18-minute sequencing duration. These results underscore NASTRAs ability to perform STR analysis on both NGS and nanopore sequencing platforms, significantly enhancing the utility of nanopore sequencing in relevant applications. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/565630v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@296e89org.highwire.dtl.DTLVardef@180b6forg.highwire.dtl.DTLVardef@96bf21org.highwire.dtl.DTLVardef@de1b1d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

One-pot virus detection based on isothermal amplificationcoupled with temperature-activated argonaute

Advances in programmable nucleases like CRISPR-associated protein (Cas) and Argonaute (Ago), combined with isothermal amplification, have made point-of-care testing (POCT) more accessible. However, the specific binding of the nuclease resulted in compatibility issues between the amplification and nuclease systems, substantially limiting the feasibility of a one-step workflow. Here, a temperature control solution based on immobilized thermotolerant Pyrococcus furiosus Ago (PfAgo) has been proposed. The use of immobilized PfAgo can effectively prevent interference with loop-mediated isothermal amplification (LAMP) at 65{degrees}C and accurately identifies amplicons when activated at 95{degrees}C. Following optimization, a sensitivity of 0.6 copies/L was achieved within 45 minutes, and high specificity was verified with no cross-reactivity among 22 other viruses. Additionally, the multiplex detection was designed for herpes virus sensing, with agreements of 86.4% for positive and 100% for negative samples. Our research presents an effective method for combining amplification and cleavage through the use of controllable nucleases, significantly improving the clinical applicability of diagnostic techniques dependent on programmable nucleases.

biochemistry↗

bioRxiv2023

Geranylgeranyl pyrophosphate (GGPP) is associated with hepatic lipid accumulation and insulin resistance in MAO by prenylating Perilipin4

Metabolically Abnormal Obesity (MAO) is characterized by hepatic steatosis and type 2 diabetes (T2D), in contrast to Metabolically Healthy Obesity (MHO). In this study, we investigated the role of hepatic geranylgeranyl pyrophosphate (GGPP), a metabolite of the mevalonate (MVA) pathway, in regulating the differences in lipid metabolism between MAO and MHO. Our findings revealed that GGPP levels were significantly elevated in individuals with MAO, and deficiency of GGPP in the liver ameliorated the defects associated with MAO. Furthermore, we discovered that the prenylation of the lipid droplet-associated protein Perilipin 4 by GGPP enhances the formation of large lipid droplets, thereby exacerbating hepatic lipid accumulation and insulin resistance. Notably, the inhibitor DGBP, targeting the GGPP synthase Ggpps, effectively attenuated the traits of MAO, offering novel insights into the treatment of this condition.

pathology↗

bioRxiv2023

Combining Bulk and Single-Cell RNA Sequencing Data to Identify RNA methylation and Autophagy-Related Signatures in Patients with Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition associated with RNA methylation and autophagy. However, the specific autophagy-related genes and RNA methylation regulators involved in COPD development remain unknown. MethodsWe analyzed COPD and non-COPD patients datasets obtained from the Gene Expression Omnibus database, including Tissue Sequencing Transcriptome (bulk-seq) and single-cell sequencing (scRNA-seq) data. Differentially expressed genes (DEGs) were identified through differential genetic analysis using non-COPD bulk-seq data as the control group and COPD samples were used as the experimental group. Animal experiments were conducted to validate the expression of key genes. COPD model mice were exposed to smoke for four months, and lung function and histopathological changes were assessed. The mRNA and protein expression levels of FTO, IGF2BP2, DDIT3, DNAJB1, and YTHDF3 were measured using RT-qPCR and Western blotting, respectively. ResultsWe identified FTO, IGF2BP2, and YTHDF3 as key methylation genes, along with autophagy hub genes DDIT3 and DNAJB1. Animal experiments showed significantly increased mRNA and protein levels of FTO, YTHDF3 and DNAJB1 and significantly decreased levels of IGF2BP2 in lung tissue of COPD mice compared to the control group. ConclusionOur findings suggest that DDIT3 and DNAJB1 as autophagy hub genes, along with FTO, IGF2BP2 and YTHDF3 as RNA methylation genes, may play crucial roles in the development of COPD. These findings, supported by bulk-seq and scRNA-seq data, contribute novel genetic evidence for understanding the epigenetics of COPD.

cell biology↗

bioRxiv2023

Spatiotemporal development of growth and death zones in expanding bacterial colonies driven by emergent nutrient dynamics

Bacterial colony growth on hard agar is commonplace in microbiology; yet, what occurs inside a growing colony is complex even in the simplest cases. Robust colony expansion kinetics featuring a linear radial growth and a saturating vertical growth indicates a common developmental program which is elucidated here for Escherichia coli cells using a combination of modeling and experiments. Radial colony expansion is found to be limited by mechanical factors rather than nutrients as commonly assumed. In contrast, vertical expansion is limited by glucose depletion inside the colony, an effect compounded by reduced growth yield due to anaerobiosis. Carbon starvation in the colony interior results in substantial cell death within 1-2 days, with a distinct death zone that expands with the growing colony. Overall, the development of simple colonies lacking EPS production and differentiation is dictated by an interplay of mechanical constraints and emergent nutrient gradients arising from obligatory metabolic processes.

microbiology↗

bioRxiv2023

Air Pollution Aggravates Renal Ischemia-Reperfusion-Induced Acute Kidney Injury

Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and declined renal function. PM2.5 exerts its harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischemia reperfusion injury (IRI) involves similar biological processes involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Mice were exposed to PM2.5 or filtered air for 12 weeks before IRI, and were euthanized 48h after IRI. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration and impaired urine concentration ability. Moreover, they showed elevated tubular damage markers NGAL and KIM-1, along with significant tubular necrosis. PM2.5 exposure exacerbated local innate immune activation, leading to an increased infiltration of Ly6G+ granulocytes and F480+ macrophages in the kidney. This, in turn, contributed to heightened renal senescence markers and myofibroblast infiltration. Collectively, our findings suggest that AKI-induced hampered tubular function is worsened by PM2.5, leading to reduced resilience to stress, activation of aging mechanisms and early hallmarks of fibrosis. Decreasing PM2.5 and implementing preventive strategies can improve AKI patients outcome and prevent AKI progression.

pathology↗

bioRxiv2023

Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity

O_LIAs phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control. C_LIO_LIWe performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae. C_LIO_LIThe Mopsd2 mutant was defective in development, lipid metabolism and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against ten phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions. C_LIO_LIOur study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent. C_LI

pathology↗

bioRxiv2023

Identification of RNA-Binding Protein Targets with HyperTRIBE in Saccharomyces cerevisiae

As a mater regulator in cells, RNA-binding protein (RBP) plays critical roles in organismal development, metabolism and various diseases. It controls gene expression at multiple levels mostly by specific recognition of target RNA. The traditional CLIP-seq method to detect transcriptome-wide RNA targets of RBP is less efficient in yeasts due to their cell walls. Here, we established an efficient HyperTRIBE (Targets of RNA-binding proteins Identified By Editing) in yeast, by fusing a RBP to the hyper active catalytic domain of human RNA editing enzyme ADAR2 and expressing the fusion protein in yeast cells. The target transcripts of RBP were marked with new RNA editing events and identified by high-throughput sequencing. We successfully applied TRIBE to identifying the RNA targets of two yeast RBPs, KHD1 and BFR1. The antibody-free HyperTRIBE has competitive advantages including low background, high sensitivity and reproducibility, and a simple library preparation procedure, which provides a reliable strategy for RBP target identification in Saccharomyces cerevisiae.

molecular biology↗

bioRxiv2022

A pan-cancer interrogation of intronic polyadenylation and its association with cancer characteristics

mRNA cleavage and polyadenylation is an integral 2-step process in the generation of protein-encoding mRNA or noncoding transcripts. More than 60% of human genes have multiple polyadenylation sites either in the 3 untranslated region (3UTR-APA) or in the intronic/exonic region, resulting in expression of isoforms with alternative polyadenylation (APA) under different physiologic conditions. The 3UTR-APAs have been extensively studied, but the biology of intronic polyadenylations (IPA) remain largely unexplored. Here we characterized the IPA profiles of 9,679 patient samples across 32 cancer types from the Cancer Genome Atlas (TCGA) cohort. Overall, we identified 22,260 detectable IPA sites; 9,014 (40.5%) occurred in all 32 cancer types and 11,676 (52.5%) occurred in 2 to 31 cancer types. By comparing tumors and their paired normal tissues, we identified 180 to 4,645 dysregulated IPAs in 132 to 2,249 genes in each of 690 patient tumors from 22 cancer types that showed consistent patterns within individual cancer types. Furthermore, across all cancer types, IPA isoforms and their gene regulation showed consistent pan-cancer patterns, and cancer types with similar histologic features were clustered at higher levels of hierarchy. We selected 2,741 genes that were consistently regulated by IPAs across cancer types, including 1,834 pan-cancer tumor-enriched and 907 tumor-depleted IPA genes. Pan-cancer tumor-enriched IPA genes were amply represented in the functional pathways such as cilium assembly and DNA damage repair. Expression of IPA isoforms in DNA damage repair genes was associated with tumor mutation burdens. Expression of IPA isoforms of tumor-enriched IPA genes was also associated with patient characteristics (e.g., sex, race, cancer stages, and subtypes) in cancer-specific and feature-specific manners. Importantly, IPA isoform expression for some genes could be a more accurate prognostic marker than gene expression (summary of all possible isoforms). In summary, our study reveals the roles and the clinical relevance of tumor-associated IPAs in cancer.

bioinformatics↗