A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling.

N6-methyladenosine (m6A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m6A demethylases such as FTO play important roles in regulating mRNA stability, splicing, and translation. Here, we demonstrate that FTO-IT1 long noncoding RNA (lncRNA) was upregulated and positively correlated with poor survival of patients with wild-type p53-expressing prostate cancer (PCa). m6A RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA m6A methylation of a subset of p53 transcriptional target genes (e.g., FAS, TP53INP1, and SESN2) and induced PCa cell cycle arrest and apoptosis. We further showed that FTO-IT1 directly binds RBM15 and inhibits RBM15 binding, m6A methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA m6A level and expression of p53 target genes and inhibited PCa growth in mice. Our study identifies FTO-IT1 lncRNA as a bona fide suppressor of the m6A methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.

Hidden codes in mRNA: Control of gene expression by m6A.

Information in mRNA has largely been thought to be confined to its nucleotide sequence. However, the advent of mapping techniques to detect modified nucleotides has revealed that mRNA contains additional information in the form of chemical modifications. The most abundant modified nucleotide is N6-methyladenosine (m6A), a methyl modification of adenosine. Although early studies viewed m6A as a dynamic and tissue-specific modification, it is now clear that the mRNAs that contain m6A and the location of m6A in those transcripts are largely universal and are influenced by gene architecture, i.e., the size and location of exons and introns. m6A can affect nuclear processes such as splicing and epigenetic regulation, but the major effect of m6A on mRNAs is to promote degradation in the cytoplasm. m6A marks a functionally related cohort of mRNAs linked to certain biological processes, including cell differentiation and cell fate determination. m6A is also enriched in other cohorts of mRNAs and can therefore affect their respective cellular processes and pathways. Future work will focus on understanding how the m6A pathway is regulated to achieve control of m6A-containing mRNAs.

Progress toward understanding chromosome silencing by Xist RNA.

The X inactive-specific transcript (Xist) gene is the master regulator of X chromosome inactivation in mammals. Xist produces a long noncoding (lnc)RNA that accumulates over the entire length of the chromosome from which it is transcribed, recruiting factors to modify underlying chromatin and silence X-linked genes in cis Recent years have seen significant progress in identifying important functional elements in Xist RNA, their associated RNA-binding proteins (RBPs), and the downstream pathways for chromatin modification and gene silencing. In this review, we summarize progress in understanding both how these pathways function in Xist-mediated silencing and the complex interplay between them.

RBM15 activates glycolysis in M1-type macrophages to promote the progression of aortic aneurysm and dissection.

Aortic aneurysm and dissection (AD) represent a critical cardiovascular emergency with an alarmingly high mortality rate. Recent research has spotlighted the overexpression of genes associated with the m6A modification in AD patients, linking them to the presence of inflammatory M1-type macrophages. Moreover, glycolysis is widely recognized as a key feature of inflammatory M1-type macrophages, but biomarkers linking glycolysis and macrophage function to promote disease progression in AD have not been reported. We conducted an analysis of aortic immune cell infiltration, macrophages, and m6A-related biomarkers in AD patients using bioinformatics techniques. Subsequently, we employed a combination of RT-PCR, WB, and immunofluorescence assays to elucidate the alterations in the expression of M1- and M2-type macrophages, as well as markers of glycolysis, following the overexpression of key biomarkers. These findings were further validated in vivo through the creation of a rat model of AD with knockdown of the aforementioned key biomarkers. The findings revealed that the m6A-modified related gene RBM15 exhibited heightened expression in AD samples and was correlated with macrophage polarization. Upon overexpression of RBM15 in macrophages, there was an observed increase in the expression of M1-type macrophage markers CXCL9 and CXCL10, alongside a decrease in the expression of M2-type macrophage markers CCL13 and MRC1. Furthermore, there was an elevation in the expression of glycolytic enzymes GLUT1 and Hexokinase, as well as HIF1α, GAPDH, and PFKFB3 after RBM15 overexpression. Moreover, in vivo knockdown of RBM15 led to an amelioration of aortic aneurysm in the rat AD model. This knockdown also resulted in a reduction of the M1-type macrophage marker iNOS, while significantly increasing the expression of the M2-type macrophage marker CD206. In conclusion, our findings demonstrate that RBM15 upregulates glycolysis in macrophages, thus contributing to the progression of AD through the promotion of M1-type macrophage polarization. Conversely, downregulation of RBM15 suppresses M1-type macrophage polarization, thereby decelerating the advancement of AD. These results unveil potential novel targets for the treatment of AD.

RBM15 Knockdown Impairs the Malignancy of Cervical Cancer by Mediating m6A Modification of Decorin.

Cervical cancer (CC) is considered to be the most prevalent female malignancies across the globe and a prime cause of mortality among women. RNA-binding motif protein 15 (RBM15) has been elucidated to participate in tumorigenesis in various cancers by regulating RNA N6-methyladenosine (m6A) methylation. However, its significance and detailed molecular mechanisms remain uncertain in CC. Using CGA database and qRT-PCR, the RBM15 expression was found to be elevated in CC tissues. After performing EdU, wound healing, Transwell migration, and xenograft tumor assays, RBM15 knockdown inhibited the malignant properties of CC cells along with the tumor development of CC cells in vivo. Moreover, qRT-PCR, MeRIP, and western blotting experiments were also confirmed that decorin (DCN) downregulated in CC was a direct substrate of RBM15 m6A methylation, and RBM15 knockdown could enhance DCN expression in CC cells. The anti-tumor effects of RBM15 knockdown could be abolished by DCN silencing. Overall, RBM15 knockdown lowered the tumorigenesis of CC both in vitro and in vivo, and it does so via mediating m6A modification of DCN mRNA in CC cells.

RBM15 suppresses hepatic insulin sensitivity of offspring of gestational diabetes mellitus mice via m6A-mediated regulation of CLDN4.

BACKGROUND: Gestational diabetes Mellitus (GDM) is a common pregnancy-specific disease with high morbidity, which is linked to a high risk of obesity and diabetes in offspring. N6-methyladenosine modification of RNA is emerging as an important epigenetic mechanism that is widely manifested in many diseases. This study aimed to investigate the mechanism of m6A methylation in metabolic syndrome in offspring result from intrauterine hyperglycemia. METHODS: GDM mice were established by feeding a high-fat diet 1 weeks before pregnancy. The m6A RNA methylation quantification kit was used to detect liver tissue methylation levels. PCR array was used to determine the expression of the m6A methylation modification enzyme. Immunohistochemistry, qRT-PCR, and western blot were used to examine the expression of RBM15, METTL13, IGF2BP1, and IGF2BP2. Subsequently, methylated RNA immunoprecipitation sequencing combined with mRNA sequencing, followed by dot blot and glucose uptake tests, were performed. RESULTS: In this study, we found that offspring from a GDM mother were more vulnerable to glucose intolerance and insulin resistance. GC-MS revealed significant metabolic changes including saturated fatty acids and unsaturated fatty acids in liver of GDM offspring. We also demonstrated that global mRNA m6A methylation level was significantly increased in the fetal liver of GDM mice, indicating epigenetic change may have a strong relationship with the mechanism of metabolism syndrome. Concordantly, RBM15, the RNA binding methyltransferase, was upregulated in the liver. In vitro, RBM15 suppressed insulin sensitivity and increased insulin resistance through m6A-regulated epigenetic inhabitation of CLDN4. Moreover, MeRIP-sequencing and mRNA-sequencing revealed that differently regulated genes with differential m6A peaks were enriched in metabolic pathways. CONCLUSION: Our study revealed the essential role of RBM15 in insulin resistance and the effect of RBM15-regulated m6A modification in the metabolic syndrome of offspring of GDM mice.

Knockdown of RBM15 inhibits tumor progression and the JAK-STAT signaling pathway in cervical cancer.

BACKGROUND: RNA binding motif protein 15 (RBM15), a writer of N6-methyladenosine (m6A) methylation, contributes significantly to the development of various tumors. However, the function of RBM15 in cervical cancer (CC) has not been determined. METHODS: Based on the GSE9750, GSE63514, and m6A datasets, m6A-related differentially expressed genes (DEGs) were screened out. The hub genes were identified by generating a Protein-Protein Interaction (PPI) network. RT-qPCR was conducted to assess the mRNA expression of hub genes. CCK8, scratch wound healing, and transwell assays were utilized to examine the influence of RBM15 on HeLa and SiHa cells. Tumor xenograft models were used to assess the effects of RBM15 on tumorigenesis. A mechanistic analysis of RBM15 in CC tumors was conducted using the GeneCards and Coxpresdb databases, followed by a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the pathway-related genes were subsequently validated using Western blotting. RESULTS: Five DEGs were screened, including WTAP, RBM15, CBLL1, and YTHDC2. Among them, WTAP, RBM15, CBLL1, and YTHDC2 were hub genes and can be used as biomarkers for CC. RBM15 expression was considerably increased, while WTAP, CBLL1, and YTHDC2 were significantly downregulated. Knockdown of RBM15 significantly suppressed the proliferation, invasion, and migration of CC cells and tumorigenesis. Moreover, knockdown of RBM15 significantly reduced the expression levels of proteins related to the JAK-STAT pathway. CONCLUSIONS: Knockdown of RBM15 inhibited the progression of CC cells, which probably by inhibiting the JAK-STAT pathway pathway.

HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition.

The mechanism of m6A modification in HPV-related cervical cancer remains unclear. This study explored the role of methyltransferase components in HPV-related cervical cancer and the mechanism. The levels of methyltransferase components and autophagy, ubiquitylation of RBM15 protein and the co-localization of lysosomal markers LAMP2A and RBM15 were measured. CCK-8 assay, flow cytometry, clone formation experiment and immunofluorescence assay were conducted to measure cell proliferation. The mouse tumor model was developed to study the cell growth in vivo. The binding of RBM15 to c-myc mRNA and m6A modifcation of c-myc mRNA were analyzed. The expressions of METTL3, RBM15 and WTAP were higher in HPV-positive cervical cancer cell lines than those in HPV-negative cells, especially RBM15. HPV-E6 knock-down inhibited the expression of RBM15 protein and promoted its degradation, but couldn't change its mRNA level. Autophagy inhibitor and proteasome inhibitor could reverse those effects. HPV-E6 siRNA could not enhance ubiquitylation modification of RBM15, but could enhance autophagy and the co-localization of RBM15 and LAMP2A. RBM15 overexpression could enhance cell proliferation, block the inhibitory effects of HPV-E6 siRNA on cell growth, and these effects could be reserved by cycloeucine. RBM15 could bind to c-myc mRNA, resulting in an increase to m6A level and protein expression of c-myc, which could be blocked by cycloeucine. HPV-E6 can downregulate autophagy, inhibit the degradation of RBM15 protein, induce the accumulation of intracellular RBM15, and increase the m6A modification on c-myc mRNA, resulting in an increase of c-myc protein and a growth promotion for cervical cancer cells.

Regulatory mechanism of RNA binding motif protein 15-mediated N6 methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells.

This study aims to explore the regulatory mechanism of RNA binding motif protein 15 (RBM15) on the proliferation, invasion, and migration of colorectal cancer (CRC) cells. RBM15, KLF1, or SIN3A expression in CRC tissues and cells was detected by RT-qPCR or Western blot. CRC cell functions were measured by CCK-8, colony formation, and Transwell assays after RBM15 intervention. MeRIP and RIP measured N6 methyladenosine (m6 A) and IGF2BP3 enrichment on KLF1 mRNA. ChIP and dual-luciferase analyzed KLF1 enrichment on SIN3A promoter. Combined experiments verified the effect of KLF1/SIN3A on CRC cell functions. Lung/liver metastasis models were established to validate the effect of RBM15 on CRC in vivo. RBM15, KLF1, and SIN3A were highly expressed in CRC. RBM15 knockdown reduced the proliferation, invasion, and migration of CRC cells in vitro. Mechanistically, RBM15 facilitated KLF1 mRNA stability and expression through IGF2BP3-dependent m6 A modification, thus promoting KLF1 enrichment on the SIN3A promoter and activating SIN3A transcription. Overexpression of KLF1 or SIN3A reversed the inhibitory effect of RBM15 knockdown on CRC cells. In vivo experiments verified that RBM15 promoted tumorigenesis and lung/liver metastasis via KLF1/SIN3A axis. In conclusion, RBM15 stimulated CRC proliferation and metastasis by promoting the KLF1/SIN3A axis through IGF2BP3-dependent m6 A modification.

N6-methyladenosine methylation regulator RBM15 promotes the progression of diabetic nephropathy by regulating cell proliferation, inflammation, oxidative stress, and pyroptosis through activating the AGE-RAGE pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world, and m6A modification plays a critical role in the progression of DN. We aimed to find m6A-related genes and their regulatory mechanisms in DN. METHODS: The expression levels of four important m6A-related genes (METTL16, RBM15, IGF2BP1, and ALKBH5) were detected by quantitative real-time PCR (RT-qPCR). RBM15 was chosen and its function was explored. The downstream pathway of RBM15 was screened by transcriptome sequencing. The levels of AGE, inflammation, and oxidative stress were determined with enzyme-linked immunosorbent assay, and the expression of AGE-RAGE pathway-related proteins were detected by Western blot (WB). Cell proliferation was assessed by Cell counting Kit-8 (CCK-8). The levels of pyroptosis-related proteins were evaluated by RT-qPCR or WB. RESULTS: METTL16 and RBM15 were up regulated in the mouse model of DN, in which RBM15 was more significant. Silencing RBM15 recovered cell proliferation, reduced the levels of inflammation factors, and inhibited cell pyroptosis in high glucose-induced HK-2 cells. Transcriptome sequencing suggested that the AGE-RAGE pathway might be downstream of RBM15. RBM15 knockdown reduced AGE level and the expression of AGE-RAGE pathway-related proteins. After silencing RBM15, we found that activating the AGE-RAGE pathway inhibited cell proliferation, increased the levels of inflammation factors, promoted oxidative stress, and induced cell pyroptosis in HK-2 cell model of DN. CONCLUSION: The m6A-related gene RBM15 inhibited cell proliferation, promoted inflammation, oxidative stress, and cell pyroptosis, thereby facilitating the progression of DN through the activation of the AGE-RAGE pathway.

RBM15 m6 A modification-mediated OTUB2 upregulation promotes cervical cancer progression via the AKT/mTOR signaling.

Cervical cancer (CC) is a deadly gynecological tumor worldwide. Otubain 2 (OTUB2) has been recently identified as an oncogene in human malignancies. However, its expression and function remain unclear. This work aims to explore the role of OTUB2 in CC progression. Herein, The Cancer Genome Atlas data revealed that OTUB2 expression was significantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and gradually increased with CESC progression; moreover, OTUB2 expression predicted poor outcomes of CESC patients. Then, RT-qPCR and Western blotting were applied to determine mRNA and protein expression in CC and normal cells. Our results confirmed that OTUB2 was highly expressed in CC cell lines. As indicated by CCK-8, Transwell, and flow cytometry results, OTUB2 silencing attenuated proliferative and metastatic capacities of CC cells but promoted CC cell apoptosis. Then, RBM15, an N6-methyladenosine (m6 A) methyltransferase "writer," was also demonstrated to be upregulated in CESC and CC cells. Mechanistically, m6 A RNA immunoprecipitation (Me-RIP) results showed that RBM15 inhibition reduced the m6 A methylation level of OTUB2 in CC cells, leading to the decline of OTUB2 expression. In addition, OTUB2 inhibition deactivated the AKT/mTOR signaling in CC cells. Furthermore, SC-79 (AKT/mTOR activator) partially abated the inhibitory effects of OTUB2 knockdown on the AKT/mTOR signaling pathway and the malignant phenotypes of CC cells. In summary, this work showed that RBM15-mediated m6 A modification led to OTUB2 upregulation, thereby promoting malignant behaviors of CC cells via the AKT/mTOR signaling pathway.

RBM15 silencing promotes ferroptosis by regulating the TGF-ß/Smad2 pathway in lung cancer.

OBJECTIVE: We assessed the function and mechanism of RNA binding motif protein 15 (RBM15) silencing in lung cancer development. METHODS: The effects of RBM15 knockdown on A549 and H1299 cells were evaluated by MTT, EdU, wound healing, and transwell assay. We then detected the functions of RBM15 silencing on lipid peroxidation, labile iron pool (LIP), ferrous iron (Fe2+ ), and ferroptosis-related genes. RNA sequencing was performed after RBM15 knockout in lung cancer cells, followed by differentially expressed genes (DEGs), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. Finally, the expression of RBM15 and pathway-related genes was determined by western blot. RESULTS: RBM15 was highly expressed in lung cancer cells. RBM15 silencing reduced the viability, inhibited cell proliferation, invasion, and migration, and suppressed tumor growth in the xenograft mouse model. Knockout of RBM15 regulated ferroptosis-related gene expression. LIP, Fe2+ , and lipid peroxidation were distinctly increased by the knockout of RBM15. RNA-seq sequencing revealed that there are 367 up-regulated and 368 down-regulated DEGs, which were enriched in molecular functions, biological processes, and cellular components. RBM15 silencing reduced the expression of TGF-ß/Smad2, and TGF-ß activator (SRI-011381) reversed the inhibitory effect of RBM15 silencing on tumor cell growth. CONCLUSION: We demonstrated that RBM15 silencing promoted ferroptosis in lung cancer cells by TGF-ß/Smad2 pathway, thereby inhibiting lung cancer cell growth, which may provide new light for lung cancer treatment.

Loss of the RNA-binding protein Rbm15 disrupts liver maturation in zebrafish.

Liver organogenesis begins with hepatic precursors in the foregut endoderm, followed by hepatoblast specification, differentiation, outgrowth, and maturation for the formation of functional hepatocytes. Although several signaling pathways and critical factors that regulate liver specification, differentiation, and proliferation have been identified, little is known about how liver maturation is regulated. Here, we used a screen for mutations affecting liver development in zebrafish and identified a cq96 mutant that exhibits a specific defect in liver maturation. Results from positional cloning revealed that cq96 encodes an RNA-binding protein, Rbm15, which is an evolutionarily conserved Spen family protein and known to play a crucial role in RNA m6A modification, nuclear export, and alternative splicing. However, a function of Rbm15 in embryonic liver development has not been reported. We found that Rbm15 is specifically expressed in the liver after its differentiation. CRISPR/Cas9-mediated loss of rbm15 repressed hepatic maturation, but did not affect hepatoblast specification, differentiation, and hepatocyte proliferation and apoptosis. Additional experiments disclosed that the mTOR complex 1 (mTORC1) pathway is highly activated in rbm15-deficient hepatocytes. Moreover, rapamycin treatment partially restored normal hepatic gene expression as well as the nuclear location of the transcription factor Hnf4a. Taken together, these results reveal an unexpected role of Rbm15 in liver maturation.

RNA-Binding Proteins in Acute Leukemias.

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

The large and small SPEN family proteins stimulate axon outgrowth during neurosecretory cell remodeling in Drosophila.

Split ends (SPEN) is the founding member of a well conserved family of nuclear proteins with critical functions in transcriptional regulation and the post-transcriptional processing and nuclear export of transcripts. In animals, the SPEN proteins fall into two size classes that perform either complementary or antagonistic functions in different cellular contexts. Here, we show that the two Drosophila representatives of this family, SPEN and Spenito (NITO), regulate metamorphic remodeling of the CCAP/bursicon neurosecretory cells. CCAP/bursicon cell-targeted overexpression of SPEN had no effect on the larval morphology or the pruning back of the CCAP/bursicon cell axons at the onset of metamorphosis. During the subsequent outgrowth phase of metamorphic remodeling, overexpression of either SPEN or NITO strongly inhibited axon extension, axon branching, peripheral neuropeptide accumulation, and soma growth. Cell-targeted loss-of-function alleles for both spen and nito caused similar reductions in axon outgrowth, indicating that the absolute levels of SPEN and NITO activity are critical to support the developmental plasticity of these neurons. Although nito RNAi did not affect SPEN protein levels, the phenotypes produced by SPEN overexpression were suppressed by nito RNAi. We propose that SPEN and NITO function additively or synergistically in the CCAP/bursicon neurons to regulate multiple aspects of neurite outgrowth during metamorphic remodeling.

The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation.

Antisense RNAs regulate the transcription and translation of the corresponding sense genes. Here, we report that an antisense RNA, AS-RBM15, is transcribed in the opposite direction within exon 1 of RBM15 RBM15 is a regulator of megakaryocyte (MK) differentiation and is also involved in a chromosome translocation t(1;22) in acute megakaryocytic leukemia. MK terminal differentiation is enhanced by up-regulation of AS-RBM15 expression and attenuated by AS-RBM15 knockdown. At the molecular level, AS-RBM15 enhances RBM15 protein translation in a CAP-dependent manner. The region of the antisense AS-RBM15 RNA, which overlaps with the 5'UTR of RBM15, is sufficient for the up-regulation of RBM15 protein translation. In addition, we find that transcription of both RBM15 and AS-RBM15 is activated by the transcription factor RUNX1 and repressed by RUNX1-ETO, a leukemic fusion protein. Therefore, AS-RBM15 is a regulator of megakaryocyte differentiation and may play a regulatory role in leukemogenesis.

Exploring the role of m 6 A writer RBM15 in cancer: a systematic review.

In the contemporary epoch, cancer stands as the predominant cause of premature global mortality, necessitating a focused exploration of molecular markers and advanced therapeutic strategies. N6-methyladenosine (m6A), the most prevalent mRNA modification, undergoes dynamic regulation by enzymes referred to as methyltransferases (writers), demethylases (erasers), and effective proteins (readers). Despite lacking methylation activity, RNA-binding motif protein 15 (RBM15), a member of the m6A writer family, assumes a crucial role in recruiting the methyltransferase complex (MTC) and binding to mRNA. Although the impact of m6A modifications on cancer has garnered widespread attention, RBM15 has been relatively overlooked. This review briefly outlines the structure and operational mechanism, and delineates the unique role of RBM15 in various cancers, shedding light on its molecular basis and providing a groundwork for potential tumor-targeted therapies.

RBM15 Protects From Myocardial Infarction by Stabilizing NAE1.

RNA-binding proteins play multiple roles in several biological processes. However, the roles of RBM15-an important RNA-binding protein and a significant regulator of RNA methylation-in cardiovascular diseases remain elusive. This study aimed to investigate the biological function of RBM15 and its fundamental mechanisms in myocardial infarction (MI). Methylated RNA immunoprecipitation sequencing was used to explore the N6-methyladenosine (m6A) difference between MI and normal tissues. Our findings showed the elevated level of m6A in MI, and its transcription profile in both MI and normal tissues. RBM15 was the main regulator and its overexpression attenuated apoptosis in cardiomyocytes and improved cardiac function in mice after MI. Then, we used one target NEDD8 activating enzyme E1 subunit and its inhibitor (MLN4924) to investigate the impact of RBM15 targets on cardiomyocytes. Finally, the enhanced m6A methylation in the presence of RBM15 overexpression led to the increased expression and stability of NEDD8 activating enzyme E1 subunit. Our findings suggest that the enhanced m6A level is a protective mechanism in MI, and RBM15 is significantly upregulated in MI and promotes cardiac function. This study showed that RBM15 affected MI by stabilizing its target on the cell apoptosis function, which might provide a new insight into MI therapy.

Identification of m6A modification patterns and RBM15 mediated macrophage phagocytosis in pancreatic cancer: An integrative analysis.

Pancreatic cancer (PC) responds weakly to conventional immunotherapy. RNA N6-methyladenosine (m6A) modification has an essential role in the immune response, while its potential role in PC tumor microenvironment (TME) immune cell infiltration remains unknown. In this study, we thoroughly assessed the m6A modification patterns of 472 PC samples using 19 m6A regulators, and we systematically correlated these modification patterns with TME immune cell infiltration characteristics. We also created the m6Ascore and evaluated the m6A modification patterns of individual tumors, identified three different m6A modification patterns, and explored the role of the important m6A "writer" RBM15 in the regulation of macrophage function in PC. Two independent PC cohorts confirmed that patients with higher m6Ascore showed significant survival benefit. We verified that knockdown of RBM15 has the ability to inhibit PC growth and to promote macrophage infiltration and enhance phagocytosis of PC cells by macrophages. In conclusion, m6A modifications play a non-negligible role in the formation of TME diversity and complexity in PC. We reveal that inhibition of RBM15 suppresses PC development and modulates macrophage phagocytosis, and provide a more effective immunotherapeutic strategy for PC.