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Circular RNAs (circRNAs) have emerged as significant regulators of cancer biology. However, the characterization and the regulatory potential of circRNAs deriving from key apoptotic genes remain poorly understood in breast cancer. We aimed to comprehensively characterize circRNAs originating from the pro-apoptotic The online version contains supplementary material available at 10.1007/s00438-026-02388-1. Show less

To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA. Show less

Increasing evidence suggests a complex interplay between psychiatric disorders and metabolic dysregulations. However, most research has been limited to specific disorder pairs, leaving a significant gap in our understanding of the broader psycho-metabolic nexus. This study leveraged large-scale cohort data and genome-wide association study (GWAS) summary statistics, covering 8 common psychiatric disorders and 43 metabolic traits. We introduced a comprehensive analytical strategy to identify shared genetic bases sequentially, from key genetic correlation regions to local pleiotropy and pleiotropic genes. Finally, we developed polygenic risk score (PRS) models to translate these findings into clinical applications. We identified significant bidirectional clinical risks between psychiatric disorders and metabolic dysregulations among 310,848 participants from the UK Biobank. Genetic correlation analysis confirmed 104 robust trait pairs, revealing 1088 key genomic regions, including critical hotspots such as chr3: 47588462-50387742. Cross-trait meta-analysis uncovered 388 pleiotropic single nucleotide variants (SNVs) and 126 shared causal variants. Among variants, 45 novel SNVs were associated with psychiatric disorders and 75 novel SNVs were associated with metabolic traits, shedding light on new targets to unravel the mechanism of comorbidity. Notably, RBM6, a gene involved in alternative splicing and cellular stress response regulation, emerged as a key pleiotropic gene. When psychiatric and metabolic genetic information were integrated, PRS models demonstrated enhanced predictive power. The study highlights the intertwined genetic and clinical relationships between psychiatric disorders and metabolic dysregulations, emphasising the need for integrated approaches in diagnosis and treatment. The National Key Research and Development Program of China (2023YFC2506200, SHH). The National Natural Science Foundation of China (82273741, SY). Show less

Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. We identified a significant genetic correlation between GERD and asthma ( rg  = 0.37, P = 6.19 × 10 -38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 -5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases. Show less

RBM6, implicated in the progression of multiple tumour types but unexplored in prostate tumours, was found to indicate potential therapeutic implications due to its elevated expression in prostate tumours. To elucidate its molecular function, scratch tests, transwell migration and invasion assays were conducted, with PCR and western blot analyses verifying molecular regulatory relationships. RNA pulldown and RNA immunoprecipitation tests were also employed to investigate underlying mechanisms. Results indicate that RBM6 enhances prostate cell migration by suppressing CDH1, yet ZEB1 overexpression alleviates this suppression. Notably, under these conditions, RBM6's inhibitory effect on MMP16 becomes more pronounced, reducing cell migration ability. Thus, under normal conditions, RBM6 promotes prostate tumour cell migration, but in the context of high ZEB1 expression, it inhibits migration. This shift in RBM6's regulatory capacity towards downstream genes underscores the importance of considering objective conditions in studying RBM6 molecules. Show less

Colorectal cancer (CRC) is a globally prevalent malignancy associated with high mortality rates. Despite the existence of various treatment modalities, the prognosis for CRC remains relatively poor. This study aims to explore the role of RNA-binding proteins (RBPs) in CRC progression and their potential as prognostic biomarkers and therapeutic targets. We first identified 166 prognosis-related RBPs, including LIN28B, PPARGC1A, RBM47, and AFF3, by performing univariate Cox regression analysis on bulk transcriptomic and clinical data from The Cancer Genome Atlas (TCGA). Next, single-cell RNA sequencing data from normal, adenoma, and CRC tissues of four patients were analyzed to determine cell type-specific expression patterns of RBPs. Ten upregulated RBPs (HSPB1, RBM47, HMGN2, BRD2, BST2, RBM6, YBX3, CANX, PLEC, and RNASET2) were identified as CRC-associated. Among them, HSPB1, RBM47, HMGN2, BRD2, BST2, and PLEC were predominantly expressed in epithelial cell subsets, whereas RNASET2, RBM6, YBX3, and G3BP2 showed higher expression in T cell subpopulations. Aberrant expression of these RBPs was significantly associated with clinical features such as age, cancer stage, and overall survival ( The online version contains supplementary material available at 10.1038/s41598-025-29678-9. Show less

The fate and functions of RNAs are coordinately regulated by RNA-binding proteins (RBPs), which are often dysregulated in various cancers. Known as a splicing regulator, RNA-binding motif protein 6 (RBM6) harbors tumor-suppressor activity in many cancers; however, there is a lack of research on the molecular targets and regulatory mechanisms of RBM6. In this study, we constructed an Using The Cancer Genome Atlas dataset, we found that higher expression of In summary, our study highlights the important role of RBM6, as well as the downstream targets and regulated pathways, suggesting the potential regulatory mechanisms of RBM6 in the development of cancer. Show less

Observational studies have preliminarily revealed an association between smoking and gastroesophageal reflux disease (GERD). However, little is known about the causal relationship and shared genetic architecture between the two. This study aims to explore their common genetic correlations by leveraging genome-wide association studies (GWAS) of smoking behavior-specifically, smoking initiation (SI), never smoking (NS), ever smoking (ES), cigarettes smoked per day (CPD), age of smoking initiation(ASI) and GERD. Firstly, we conducted global cross-trait genetic correlation analysis and heritability estimation from summary statistics (HESS) to explore the genetic correlation between smoking behavior and GERD. Then, a joint cross-trait meta-analysis was performed to identify shared "pleiotropic SNPs" between smoking behavior and GERD, followed by co-localization analysis. Additionally, multi-marker analyses using annotation (MAGMA) were employed to explore the degree of enrichment of single nucleotide polymorphism (SNP) heritability in specific tissues, and summary data-based Mendelian randomization (SMR) was further utilized to investigate potential functional genes. Finally, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the smoking behavior and GERD. Consistent genetic correlations were observed through global and local genetic correlation analyses, wherein SI, ES, and CPD showed significantly positive genetic correlations with GERD, while NS and ASI showed significantly negative correlations. HESS analysis also identified multiple significantly associated loci between them. Furthermore, three novel "pleiotropic SNPs" (rs4382592, rs200968, rs1510719) were identified through cross-trait meta-analysis and co-localization analysis to exist between SI, NS, ES, ASI, and GERD, mapping the genes MED27, HIST1H2BO, MAML3 as new pleiotropic genes between SI, NS, ES, ASI, and GERD. Moreover, both smoking behavior and GERD were found to be co-enriched in multiple brain tissues, with GMPPB, RNF123, and RBM6 identified as potential functional genes co-enriched in Cerebellar Hemisphere, Cerebellum, Cortex/Nucleus accumbens in SI and GERD, and SUOX identified in Caudate nucleus, Cerebellum, Cortex in NS and GERD. Lastly, consistent causal relationships were found through MR analysis, indicating that SI, ES, and CPD increase the risk of GERD, while NS and higher ASI decrease the risk. We identified genetic loci associated with smoking behavior and GERD, as well as brain tissue sites of shared enrichment, prioritizing three new pleiotropic genes and four new functional genes. Finally, the causal relationship between smoking behavior and GERD was demonstrated, providing insights for early prevention strategies for GERD. Show less

Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%). Show less

Pancreatic adenocarcinoma (PAAD) is one of the most malignancy diseases. Lysine β-hydroxybutyrylation (Kbhb) has been reported to involve various metabolism and cancer progression. Data from online databases (TCGA and GEO) were retrieved for the selection of differential expressed Kbhb site genes (DTRGs). Univariate cox and LASSO analysis were performed to identify the prognostic DTRGs. Based on the optimal DTRGs, a prognostic risk score model was established. Kaplan-Meier and Receiver operator characteristic analysis were conducted to evaluate the predicting ability of the prognosis model. Generated with clinical data, independent analysis and nomogram model were performed. Finally, the differences of survival, immune cell levels, immunotherapy response, drug sensitivity between high- and low-risk groups were explored. A total of 63 DTRGs were identified in PAAD, and these genes were related to cell division and apoptosis biological functions. Through univariate cox regression and LASSO analysis, 30 DTRGs were selected to be related to prognosis and five ( A five-gene prognosis risk model which exhibit promising predictive ability in survival is constructed for patients with PAAD. Show less

Glioma is a highly invasive brain cancer that is difficult to treat due to its complex molecular characteristics and poor prognosis. The COVID-19 pandemic has introduced additional clinical challenges for cancer patients, especially those with glioma. This study explored the molecular interactions between glioma and COVID-19 using integrated bioinformatics methods, including enrichment analysis, survival analysis, and molecular docking, focusing on the PI3K-Akt signaling pathway and the immunomodulatory role of vitamin D. From gene expression data of glioma and COVID-19, 203 common differentially expressed genes were identified, and six prognostic key genes-MYBL2, RBM6, VEPH1, AHNAK2, GNG10, and DUSP14-were further determined. After intersecting with vitamin D targets five prognostic key genes were determined-MYBL2, RBM6, VEPH1, AHNAK2 and GNG10. These genes play significant roles in the PI3K-Akt pathway and potentially interact with vitamin D. Molecular docking and single-cell RNA sequencing analyses suggest that vitamin D may improve the prognosis of glioma patients infected with COVID-19 by regulating these key genes and the PI3K-Akt pathway. The findings reveal molecular links between glioma and COVID-19, thereby providing new insights for developing targeted therapeutic strategies. Show less

Osteoarthritis (OA) entails a prevalent chronic ailment, marked by the widespread involvement of entire joints. Prolonged low-grade synovial inflammation serves as the key instigator for a cascade of pathological alterations in the joints. The study seeks to explore potential therapeutic targets for OA and investigate the associated mechanistic pathways. Summary-level data for OA were downloaded from the genome-wide association studies (GWAS) database, expression quantitative trait loci (eQTL) data were acquired from the eQTLGen consortium, and synovial chip data for OA were obtained from the GEO database. Following the integration of data and subsequent Mendelian randomization analysis, differential analysis, and weighted gene co-expression network analysis (WGCNA) analysis, core genes that exhibit a significant causal relationship with OA traits were pinpointed. Subsequently, by employing three machine learning algorithms, additional identification of gene targets for the complexity of OA was achieved. Additionally, corresponding ROC curves and nomogram models were established for the assessment of clinical prognosis in patients. Finally, western blotting analysis and ELISA methodology were employed for the initial validation of marker genes and their linked pathways. Twenty-two core genes with a significant causal relationship to OA traits were obtained. Through the application of distinct machine learning algorithms, MAT2A and RBM6 emerged as diagnostic marker genes. ROC curves and nomogram models were utilized for evaluating both the effectiveness of the two identified marker genes associated with OA in diagnosis. MAT2A governs the synthesis of SAM within synovial cells, thereby thwarting synovial fibrosis induced by the TGF-β1-activated Smad3/4 signaling pathway. The first evidence that MAT2A and RBM6 serve as robust diagnostic for OA is presented in this study. MAT2A, through its involvement in regulating the synthesis of SAM, inhibits the activation of the TGF-β1-induced Smad3/4 signaling pathway, thereby effectively averting the possibility of synovial fibrosis. Concurrently, the development of a prognostic risk model facilitates early OA diagnosis, functional recovery evaluation, and offers direction for further therapy. Show less

Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment. Using the GEO dataset, we screened differentially expressed genes (DEGs) in asthma patients' blood. Employing Summary Data-based Mendelian Randomization (SMR) and Two-Sample Mendelian Randomization (TSMR), we pinpointed asthma causal genes, causal DNA methylation sites, and methylation sites affecting gene expression, cross validated with at least 2 large-scale GWAS from each source. We utilized colocalization for genetic associations, meta-analysis for data integration, two-step MR for methylation-gene-asthma mediation mechanism. Druggability was evaluated using Open Target, virtual screening, and docking. Among the 954 DEGs found in asthma patients' blood, increased expression of CEP95 (discovery, OR_SMR = 0.94, 95% CI: 0.91-0.97), RBM6 (discovery, OR_SMR = 0.97, 95% CI: 0.95-0.99), and ITPKB (discovery, OR_SMR = 0.82, 95% CI: 0.74-0.92) in the blood decreased the risk of asthma, higher levels of HOXB-AS1 (discovery, OR_SMR = 1.05, 95% CI: 1.03-1.07), ETS1 (discovery, OR_SMR = 1.62, 95% CI: 1.29-2.04), and JAK2 (discovery, OR_SMR = 1.13, 95% CI: 1.06-1.21) in the blood increased the risk of asthma. Additionally, a total of 8 methylation sites on ITPKB, ETS1, and JAK2 were identified to influence asthma. An increase in methylation at site cg16265553 raised the risk of asthma partially by suppressing ITPKB expression. Similarly, increased methylation at cg13661497 reduced the asthma risk totally by suppressing JAK2 expression. The impact of CEP95, HOXB-AS1, and RBM6 expressions on asthma was further confirmed in lung tissues. Except for HOXB-AS1, all the other genes were potential druggable targets. Our study highlighted that specific gene expressions and methylation sites significantly influence asthma risk and revealed a potential methylation-to-gene-to-asthma mechanism. This provided pivotal evidence for future targeted functional studies and the development of preventive and treatment strategies. Show less

DNA double-strand breaks (DSBs) are highly toxic lesions that threaten genome integrity and cell survival. To avoid harmful repercussions of DSBs, a wide variety of DNA repair factors are recruited to execute DSB repair. Previously, we demonstrated that RBM6 splicing factor facilitates homologous recombination (HR) of DSB by regulating alternative splicing-coupled nonstop-decay of the HR protein APBB1/Fe65. Here, we describe a splicing-independent function of RBM6 in promoting HR repair of DSBs. We show that RBM6 is recruited to DSB sites and PARP1 activity indirectly regulates RBM6 recruitment to DNA breakage sites. Deletion mapping analysis revealed a region containing five glycine residues within the G-patch domain that regulates RBM6 accumulation at DNA damage sites. We further ascertain that RBM6 interacts with Rad51, and this interaction is attenuated in RBM6 mutant lacking the G-patch domain (RBM6 Show less

Hypertension is a leading risk factor of cardiovascular disease and mortality in the population worldwide. Recently, hundreds of genomic loci were reported for hypertension by GWAS, however, the most SNPs are located in intergenic regions of genome, where a functional cause is difficult to determine. In the current study, a TWAS of hypertension was conducted using 452,264 individuals including 84,640 patients. KEGG and GO enrichment analyses were performed for the hypertension-related genes identified via TWAS. PPI network analysis based on the STRING database was also performed to detect TWAS-identified genes in hypertension. We have identified 18,420 genes from the GWAS summary data, and of those 1010 non-overlapping genes expression were significantly associated with hypertension after FDR correction (PFDR <0.05) in four tissues (left heart ventricle, aorta, whole blood, and peripheral blood). The KEGG and GO terms were mostly related to autoimmune mechanisms, and the autoimmune-related pathways have also been enriched using GO analysis for PPI genes. We further performed Mendelian randomization analysis, and the results supported a significant association between autoimmunity and hypertension. Moreover, 15 novel hypertension-susceptible genes were identified in all tissues, and five of the genes ( Show less

To investigate whether RBM6 can serve as a suppressor gene in hepatocellular carcinoma (HCC) and affect its progression. QPCR and Western blot were carried out to measure RBM6 expression in tissue samples collected from HCC patients with different tumor sizes or in different stages. The relationship between overall survival (OS) and RBM6 expression in patients with HCC was analyzed using Kaplan-Meier survival method. Meanwhile, the effects of different factors on HCC progression were evaluated through Cox regression analysis. After over-expression of RBM6 in HepG2 and HB611 cells, the cell viability, cell migration and invasion abilities and apoptosis rate were assessed by cell counting kit-8 (CCK-8), transwell assay, and flow cytometry analysis, respectively. RBM6 expression, markedly down-regulated in HCC tissues, showed a great relevance to tumor size, TNM stage, and histological grade, and the survival rate of patients in high RBM6 expression group was higher than those in low RBM6 expression group. Besides, Cox regression analysis revealed that RBM6 expression, tumor size, TNM stage and histological grade were four independent factors affecting the OS of HCC patients. Moreover, in vitro cell experiments demonstrated that overexpression of RBM6 significantly attenuated the cell viability as well as the invasive ability while enhanced cell apoptosis. The low expression of RBM6 contributes to the improvement of the survival of patients with HCC. Therefore, RBM6 can serve as a tumor-suppressing gene to repress cell proliferation, migration and invasion and promote cell apoptosis, thereby affecting the progression of HCC. Show less

RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors. Show less

The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female genital tumors, osteosarcoma, and other malignant tumors. It can inhibit proliferation, promote apoptosis, and inhibit invasion and metastasis. RBM10 has long been considered a tumor suppressor because it promotes apoptosis through the regulation of the MDM2-p53 negative feedback loop, Bcl-2, Bax, and other apoptotic proteins and inhibits proliferation through the Notch signaling and rap1a/Akt/CREB pathways. However, it has been recently demonstrated that RBM10 can also promote cancer. Given these different views, it is necessary to summarize the research progress of RBM10 in various fields to reasonably analyze the underlying molecular mechanisms, and provide new ideas and directions for the clinical research of RBM10 in various cancer types. In this review, we provide a new perspective on the reasons for these opposing effects on cancer biology, molecular mechanisms, research progress, and clinical value of RBM10. Show less

Bone regeneration and remodeling are complex physiological processes that are regulated by key transcription factors. Understanding the regulatory mechanism of key transcription factors on the osteogenic differentiation of mesenchymal stem cells (MSCs) is a key issue for successful bone regeneration and remodeling. In the present study, we investigated the regulatory mechanism of the histone deacetylase Sirtuin 7 (SIRT7) on the key transcription factor OSX and osteogenesis of MSCs. In this study, we found that SIRT7 knockdown increased ALP activity and in vitro mineralization and promoted the expression of the osteogenic differentiation markers DSPP, DMP1, BSP, OCN, and the key transcription factor OSX in MSCs. In addition, SIRT7 could associate with RNA binding motif protein 6 (RBM6) to form a protein complex. Moreover, RBM6 inhibited ALP activity, the expression of DSPP, DMP1, BSP, OCN, and OSX in MSCs, and the osteogenesis of MSCs in vivo. Then, the SIRT7/RBM6 protein complex was shown to downregulate the level of H3K18Ac in the OSX promoter by recruiting SIRT7 to the OSX promoter and inhibiting the expression of OSX isoforms 1 and 2. Furthermore, lncRNA PLXDC2-OT could associate with the SIRT7/RBM6 protein complex to diminish its binding and deacetylation function in the OSX promoter and its inhibitory function on OSX isoforms 1 and 2 and to promote the osteogenic potential of MSCs. Show less

RBM10 is a nuclear RNA-binding protein (RBP) that regulates the alternative splicing of primary transcripts. Recently, research on RBM10 has become increasingly active owing to its clinical importance, as indicated by studies on RBM0 mutations that cause TARP syndrome, an X-linked congenital pleiotropic developmental anomaly, and various cancers such as lung adenocarcinoma in adults. Herein, the molecular biology of RBM10 and its significance in medicine are reviewed, focusing on the gene and protein structures of RBM10, its cell biology, molecular functions and regulation, relationship with the paralogous protein RBM5, and the mutations of RBM10 and their associated diseases. Finally, the challenges in future studies of RBM10 are discussed in the concluding remarks. Show less

Vascular endothelial growth factor A (VEGFA) gene has three alternative exons which results in multiple isoforms. VEGFA has been found overexpressed in patients with endometrial cancer, but the VEGFA expression pattern and how it is regulated are still unknown. The level of VEGFA transcripts and protein isoforms were detected by semi-quantitative Polymerase chain reaction (PCR) and immunoblotting in 29 paired endometrial tumor and adjacent nontumor control tissues. The level of three alternative splicing related proteins: RBM5, RBM6, and RBM10 was determined by immunoblotting. The H3K27Ac level in RBM10 promoter region was detected by ChIP-PCR. The RBM10 promoter region methylation level were quantified by methylation-sensitive high resolution melting. VEGFA165a was overexpressed and VEGFA165b level was reduced in tumors. RBM10 level was reduced in tumors. RBM10 level was negatively correlated with VEGFA165a level and positively correlated with VEGFA165b level in tumors. Using HEC-1-A and RL95-2 cells, we confirmed that VEGFA165a/b expressed pattern was controlled by RBM10. MALAT1 level was increased in tumors but not involved in VEGFA alternative splicing. Reduced H3K27Ac level and increased DNA methylation in the promoter region controlled RBM10 expression in tumors. VEGFA alternative splicing in endometrial cancer was regulated by RBM10, the expression of which was controlled by histone acetylation and DNA methylation. Show less

Numb is a conserved protein plays important roles in the development of cancer. Two Numb isoforms have been found produced by alternative splicing and play contrast roles in regulating cellular functions. It is reported that the expression of Numb long isoform (Numb-L) was increased in various kinds of cancers, but in endometrial cancer, the condition is still unknown. The level of two Numb transcripts and protein isoforms were detected by semiquantitative polymerase chain reaction and immunoblotting in 47 paired endometrial tumor and adjacent non-tumor control tissues. The level of three alternative splicing related proteins: RBM5, RBM6, and RBM10 was determined by immunoblotting. MiRNAs targeting RBM10 were predicted by bioinformatics tools and their interaction with RBM10 was confirmed by luciferase assay and immunoblotting. The function of miR-335 in endometrial cancer was examined in xenograft mouse model. Numb-L level was increased in tumors and negatively correlated with RBM10 protein level. RBM10 mRNA level was not significantly altered in endometrial tumors suggesting its expression may regulated by post transcriptional regulators such as miRNAs. We identified miR-133a, miR-133b, and miR-335 directly target RBM10, but only miR-335 level increased in tumors and negatively correlated with RBM10 protein level. miR-335 overexpression promoted tumor growth by downregulating RBM10 and upregulating Numb-L level in xenograft mouse model. miR-335 overexpression promoted Numb-L expression via targeting RBM10 in endometrial cancer, which may provide new biomarkers for EC diagnosis. Show less

Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation. Show less

Lung cancer has the highest mortality rate of all cancers worldwide. Lung cancer is a very heterogeneous disease that is often diagnosed at later stages which have a poor prognosis. Aberrant alternative splicing patterns found in lung cancer contribute to important cell functions. These include changes in splicing for the BCL2L1, MDM2, MDM4, NUMB and MET genes during lung tumourigenesis, to affect pathways involved in apoptosis, cell proliferation and cellular cohesion. Global analyses of RNASeq datasets suggest there may be many more potentially influential aberrant splicing events that need to be investigated in lung cancer. Changes in expression of the splicing factors that regulate alternative splicing events have also been identified in lung cancer. Of these, changes in expression of QKI, RBM4, RBM5, RBM6, RBM10 and SRSF1 proteins regulate many of the most frequently referenced aberrant splicing events in lung cancer. The expanding list of genes known to be aberrantly spliced in lung cancer along with the altered expression of splicing factors that regulate them are providing new clues as to how lung cancer develops, and how these events can be exploited for better treatment. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm. Show less

Early diagnosis is crucial to improve outcomes for pancreatic cancer patients (PC). The present study is designed to identify differently expressed peptides involved in PC as potential biomarkers. The serum proteome of 22 PC patients, 12 pancreatitis patients (PP), and 45 healthy controls (HC) are analyzed using magnetic bead-based weak cation exchange (MB-WCX) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Next, a supervised neural network (SNN) algorithm model is established by ClinProTools and the candidate biomarker identified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Finally, the candidate biomarker is validated in tissue samples. The SNN algorithm model discriminates PC from HC with 92.97% sensitivity and 94.55% specificity. Seventy-six differentially expressed peptides are identified, seven of which are significantly different among PC, PP, and HC (p < 0.05). Only one peak (m/z: 1466.99) tends to be upregulated in samples from HC, PP, and PC, which is identified as region of RNA-binding motif protein 6 (RBM6). In subsequent tissue analysis, it is verified that RBM6 expression is significantly higher in PC tissues than paracancerous tissue. The results indicate that RBM6 might serve as a candidate diagnostic biomarker for PC. Methods used in this study could generate serum peptidome profiles of PC, PP, and HC, and present an approach to identify potential biomarkers for diagnosis of this malignancy. Show less

Aberrant expression of RBM6 has been implicated in the development of human malignancies. However, the bio-function of RBM6 in laryngocarcinoma is still almost blank. Here we identified that RBM6 was downregulated in laryngocarcinoma tissues, as well as laryngocarcinoma cell lines. Notably, the expression level of RBM6 was lower in laryngocarcinoma patients at stage3/4 than that in laryngocarcinoma patients at stage1/2. Upregulation of RBM6 suppressed the proliferation of TU212 and Hep-2 cells, as shown by decreased cell viability and Ki67 level. In parallel, overexpression of RBM6 inhibited invasion and promoted apoptosis of TU212 and Hep-2 cells, as evidenced by downregulation of MMP-2 and MMP-9 protein expression and upregulation of cleaved caspase-3 protein expression. In vivo, RBM6 overexpression repressed the laryngocarcinoma tumor growth. EGFR mRNA level was higher in the laryngocarcinoma tissues than that in the adjacent normal tissues. Moreover, upregulation of RBM6 reduced the expression of EGFR, ERK and p-ERK in vitro and in vivo. Our data suggest that RBM6 as a tumor suppressor represses the growth and progression in laryngocarcinoma. Show less

Splicing factor RBM10 and its close homologues RBM5 and RBM6 govern the splicing of oncogenes such as Fas, NUMB, and Bcl-X. The molecular architecture of these proteins includes zinc fingers (ZnFs) and RNA recognition motifs (RRMs). Three of these domains in RBM10 that constitute the RNA binding part of this splicing factor were found to individually bind RNAs with micromolar affinities. It was thus of interest to further investigate the structural basis of the well-documented high-affinity RNA recognition by RMB10. Here, we investigated RNA binding by combinations of two or three of these domains and discovered that a polypeptide containing RRM1, ZnF1, and RRM2 connected by their natural linkers recognizes a specific sequence of the Fas exon 6 mRNA with an affinity of 20 nM. Nuclear magnetic resonance structures of the RBM10 domains RRM1 and ZnF1 and the natural V354del isoform of RRM2 further confirmed that the interactions with RNA are driven by canonical RNA recognition elements. The well-known high-fidelity RNA splice site recognition by RBM10, and probably by RBM5 and RBM6, can thus be largely rationalized by a cooperative binding action of RRM and ZnF domains. Show less

The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan. Show less

The mechanisms that underlie the association between obesity and type 2 diabetes are not fully understood. Here, we investigated the role of the 3D genome organization in the pathogeneses of obesity and type-2 diabetes. We interpreted the combined and differential impacts of 196 diabetes and 390 obesity associated single nucleotide polymorphisms (SNPs) by integrating data on the genes with which they physically interact (as captured by Hi-C) and the functional [i.e., expression quantitative trait loci (eQTL)] outcomes associated with these interactions. We identified 861 spatially regulated genes (e.g., Show less