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N6-methyladenosine modulates long non-coding RNA in the developing mouse heart.

ABSTRACT: Long non-coding RNAs (lncRNAs) were reported to potentially play a regulatory role in the process of myocardial regeneration in the neonatal mouse. N6-methyladenosine (m⁶A) modification may play a key role in myocardial regeneration in mice and regulates a variety of biological processes through affecting the stability of lncRNAs. However, the map of m⁶A modification of lncRNAs in mouse cardiac development still remains unknown. We aimed to investigate the differences in the m⁶A status of lncRNAs during mouse cardiac development and reveal a potential role of m⁶A modification modulating lncRNAs in cardiac development and myocardial regeneration during cardiac development in mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of the heart tissue in C57BL/6 J mice at postnatal day 1 (P1), P7 and P28 were performed to produce stagewise cardiac lncRNA m⁶A-methylomes in a parallel timeframe with the established loss of an intrinsic cardiac regeneration capacity and early postnatal development. There were significant differences in the distribution and abundance of m⁶A modifications in lncRNAs in the P7 vs P1 mice. In addition, the functional role of m⁶A in regulating lncRNA levels was established for selected transcripts with METTL3 silencing in neonatal cardiomyocytes in vitro. Based on our MeRIP-qPCR experiment data, both lncGm15328 and lncRNA Zfp597, that were not previously associated with cardiac regeneration, were found to be the most differently methylated at P1-P7. These two lncRNAs sponged several miRNAs which further regulated multiple mRNAs, including some of which have previously been linked with cardiac regeneration ability. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differential m⁶A modifications were more enriched in functions and cellular signalling pathways related to cardiomyocyte proliferation. Our data suggested that the m⁶A modification on lncRNAs may play an important role in the regeneration of myocardium and cardiac development.

SUBMITTER: Shen S

PROVIDER: S-EPMC9300643 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBladder cancer (BLCA) typically has a poor prognosis due to high relapse and metastasis rates. A growing body of evidence indicates that N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play crucial roles in the progression of BLCA and the treatment response of patients with BLCA. Therefore, we conducted a comprehensive RNA-seq analysis of BLCA using data from The Cancer Genome Atlas (TCGA) to establish an m6A-related lncRNA prognostic signature (m6A-RLPS) for BLCA.MethodsConsensus clustering analysis was used to investigate clusters of BLCA patients with varying prognoses. The least absolute shrinkage and selection operator Cox regression were used to develop the m6A-RLPS. The ESTIMATE and CIBERSORT algorithms were used to evaluate the immune composition.ResultsA total of 745 m6A-related lncRNAs were identified using Pearson correlation analysis (|R| > 0.4, p < 0.001). Fifty-one prognostic m6A-related lncRNAs were screened using univariate Cox regression analysis. Through consensus clustering analysis, patients were divided into two clusters (clusters 1 and 2) with different overall survival rates and tumor stages based on the differential expression of the lncRNAs. Enrichment analysis demonstrated that terms related to tumor biological processes and immune-related activities were increased in patient cluster 2, which was more likely to exhibit low survival rates. Nine m6A-related prognostic lncRNAs were finally determined and subsequently used to construct the m6A-RLPS, which was verified to be an independent predictor of prognosis using univariate and multivariate Cox regression analyses. Further, a nomogram based on age, tumor stage, and the m6A-RLPS was generated and showed high accuracy and reliability with respect to predicting the survival outcomes of BLCA patients. The prognostic signature was found to be strongly correlated to tumor-infiltrating immune cells and immune checkpoint expression.ConclusionsWe established a novel m6A-RLPS with a favorable prognostic value for patients with BLCA. We believe that this prognostic signature can provide new insights into the tumorigenesis of BLCA and predict the treatment response in patients with BLCA.

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N6-methyladenosine modulates long non-coding RNA in the developing mouse heart.

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