Dynamic Expression of m6A Regulators During Multiple Human Tissue Development and Cancers.
26 Jan 2021-Frontiers in Cell and Developmental Biology (Frontiers Media SA)-Vol. 8, pp 629030-629030
TL;DR: Wang et al. as mentioned in this paper comprehensively analyzed the dynamic expression alterations of m6A regulators during seven tissue development and eight cancer types, and found that m6a regulators globally exhibited decreased expression during development, suggesting an oncofetal reprogramming in cancer.
Abstract: N6-methyladenosine (m6A) plays critical roles in human development and cancer progression. However, our knowledge regarding the dynamic expression of m6A regulators during human tissue development is still lacking. Here, we comprehensively analyzed the dynamic expression alterations of m6A regulators during seven tissue development and eight cancer types. We found that m6A regulators globally exhibited decreased expression during development. In addition, IGF2BP1/2/3 (insulinlike growth factor 2 MRNA-binding protein 1/2/3) exhibited reverse expression pattern in cancer progression, suggesting an oncofetal reprogramming in cancer. The expressions of IGF2BP1/2/3 were regulated by genome alterations, particularly copy number amplification in cancer. Clinical association analysis revealed that higher expressions of IGF2BP1/2/3 were associated with worse survival of cancer patients. Finally, we found that genes significantly correlated with IGF2BP1/2/3 were significantly enriched in cancer hallmark-related pathways. In summary, dynamic expression analysis will guide both mechanistic and therapeutic roles of m6A regulators during tissue development and cancer progression.
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TL;DR: The similarity between embryogenesis, inflammation and tumorigenesis is discussed, and the mechanisms of oncofetal reprogramming that enable tumour cells to escape from immune responses, promoting tumour growth and metastasis are described.
13 citations
TL;DR: In this paper , the authors investigated common features of alterations in m6A modification and m6a-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort.
Abstract: Abstract N 6 -Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial–mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.
3 citations
TL;DR: In this article, the authors build a transcriptome-wide m6A methylome during the osteogenic differentiation of human adipose-derived stem cells (hASCs) using MeRIP-seq and RNA-seq.
Abstract: Adipose-derived stem cells are frequently used for bone regeneration both in vitro and in vivo. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification on eukaryotic RNAs and plays multifaceted roles in development and diseases. However, the regulatory mechanisms of m6A in osteogenic differentiation of human adipose-derived stem cells (hASCs) remain elusive. The present study aimed to build the transcriptome-wide m6A methylome during the osteogenic differentiation of hASCs. hASCs were harvested after being cultured in a basic or osteogenic medium for 7 days, and the osteogenic differentiation was validated by alkaline phosphatase (ALP) and Alizarin Red S staining, ALP activity assay, and qRT-PCR analysis of ALP, RUNX2, BGLAP, SPP1, SP7, and COL1A1 genes. The m6A level was colorimetrically measured, and the expression of m6A regulators was confirmed by qRT-PCR and western blot. Moreover, m6A MeRIP-seq and RNA-seq were performed to build the transcriptome and m6A methylome. Furthermore, bioinformatic analyses including volcano plots, Venn plots, clustering analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, gene sets enrichment analysis, and protein-protein interaction analysis were conducted. In total, 1145 differentially methylated peaks, 2261 differentially expressed genes, and 671 differentially methylated and expressed genes (DMEGs) were identified. GO and KEGG pathway analyses conducted for these DMEGs revealed extensive and osteogenic biological functions. The “PI3K-Akt signaling pathway”; “MAPK signaling pathway”; “parathyroid hormone synthesis, secretion, and action”; and “p53 signaling pathway” were significantly enriched, and the DMEGs in these pathways were identified as m6A-specific key genes. A protein-protein interaction network based on DMEGs was built, and VEGFA, CD44, MMP2, HGF, and SPARC were speculated as the hub DMEGs. The total m6A level was reduced with osteogenic differentiation of hASCs. The transcriptome-wide m6A methylome built in the present study indicated quite a few signaling pathways, and hub genes were influenced by m6A modification. Future studies based on these epigenetic clues could promote understanding of the mechanisms of osteogenic differentiation of hASCs.
3 citations
TL;DR: In this article , the role of m 6A modifications in cellular senescence with regard to oxidative stress, DNA damage, telomere alterations, and SASP development is discussed.
Abstract: Cellular senescence is a state of irreversible cellular growth arrest that occurs in response to various stresses. In addition to exiting the cell cycle, senescent cells undergo many phenotypic alterations, including metabolic reprogramming, chromatin rearrangement, and senescence-associated secretory phenotype (SASP) development. Furthermore, senescent cells can affect most physiological and pathological processes, such as physiological development; tissue homeostasis; tumour regression; and age-associated disease progression, including diabetes, atherosclerosis, Alzheimer's disease, and hypertension. Although corresponding anti-senescence therapies are actively being explored for the treatment of age-associated diseases, the specific regulatory mechanisms of senescence remain unclear. N 6-methyladenosine (m 6A), a chemical modification commonly distributed in eukaryotic RNA, plays an important role in biological processes such as translation, shearing, and RNA transcription. Numerous studies have shown that m 6A plays an important regulatory role in cellular senescence and aging-related disease. In this review, we systematically summarize the role of m 6A modifications in cellular senescence with regard to oxidative stress, DNA damage, telomere alterations, and SASP development. Additionally, diabetes, atherosclerosis, and Alzheimer's disease regulation via m 6A-mediated cellular senescence is discussed. We further discuss the challenges and prospects of m 6A in cellular senescence and age-associated diseases with the aim of providing rational strategies for the treatment of these age-associated diseases.
References
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
34,830 citations
TL;DR: A practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics, which makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries.
Abstract: The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
10,947 citations
TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
7,997 citations
TL;DR: A combination of automated approaches and expert curation is used to develop a collection of "hallmark" gene sets, derived from multiple "founder" sets, that conveys a specific biological state or process and displays coherent expression in MSigDB.
Abstract: The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of “hallmark” gene sets as part of MSigDB. Each hallmark in this collection consists of a “refined” gene set, derived from multiple “founder” sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.
6,062 citations
John N. Weinstein1, John N. Weinstein2, Eric A. Collisson3, Gordon B. Mills1 +376 more•Institutions (31)
TL;DR: The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA with a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages.
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