Regulatory Role of N6-methyladenosine (m6A) Modification in Osteosarcoma.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8170137 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Osteoporosis is a metabolic skeletal disorder in which bone mass is depleted and bone structure is destroyed to the degree that bone becomes fragile and prone to fractures. Emerging evidence suggests that N6-methyladenosine (m6A) modification, a novel epitranscriptomic marker, has a significant role in bone development and metabolism. M6A modification not only participates in bone development, but also plays important roles as writers and erasers in the osteoporosis. M6A methyltransferase METTL3 and demethyltransferase FTO involves in the delicate process between adipogenesis differentiation and osteogenic differentiation, which is important for the pathological development of osteoporosis. Conditional knockdown of the METTL3 in bone marrow stem cells (BMSCs) could suppress PI3K-Akt signaling, limit the expression of bone formation-related genes (such as Runx2 and Osterix), restrain the expression of vascular endothelial growth factor (VEGF) and down-regulate the decreased translation efficiency of parathyroid hormone receptor-1 mRNA. Meanwhile, knockdown of the METTL3 significantly promoted the adipogenesis process and janus kinase 1 (JAK1) protein expression via an m6A-dependent way. Specifically, there was a negative correlation between METTL3 expression and porcine BMSCs adipogenesis. The evidence above suggested that the relationship between METTL3 expression and adipogenesis was inverse, and osteogenesis was positive, respectively. Similarly, FTO regulated for BMSCs fate determination during osteoporosis through the GDF11-FTO-PPARγ axis, prompting the shift of MSC lineage commitment to adipocyte and inhibiting bone formation during osteoporosis. In this systematic review, we summarize the most up-to-date evidence of m6A RNA modification in osteoporosis and highlight the potential role of m6A in prevention, treatment, and management of osteoporosis.
| S-EPMC6965011 | biostudies-literature
Project description:N6-Methyladenosine (m6A) is the most abundant, dynamic, and reversible epigenetic RNA modification that is found in coding and non-coding RNAs. Emerging studies have shown that m6A and its regulators affect multiple steps in RNA metabolism and play broad roles in various cancers. Worldwide, breast cancer is the most prevalent cancer in female. It is a very heterogeneous disease characterized by genetic and epigenetic variations in tumor cells. Increasing evidence has shown that the dysregulation of m6A-related effectors, as methyltransferases, demethylases, and m6A binding proteins, is pivotal in breast cancer pathogenesis. In this review, we have summarized the most up-to-date research on the biological functions of m6A modification in breast cancer and have discussed the potential clinical applications and future directions of m6A modification as a biomarker as well as a therapeutic target of breast cancer.
| S-EPMC7690038 | biostudies-literature
Project description:RNA modifications have emerged as key regulators of transcript expression in diverse physiological and pathological processes. As one of the most prevalent types of RNA modifications, N6-methyladenosine (m6A) has become the highlight in modulation of various diseases through interfering RNA splicing, translation, nuclear export, and decay. In many cases, the detailed functions of m6A in cellular processes and diseases remain unclear. Notably, recent studies have determined the relationship between m6A modification and musculoskeletal disorders containing osteosarcoma, osteoarthritis, rheumatoid arthritis, osteoporosis, etc. Herein, this review comprehensively summarizes the recent advances of m6A modification in pathogenesis and progression of musculoskeletal diseases. Specifically, the underlying molecular mechanisms, detection technologies, regulatory functions, clinical implications, and future perspectives of m6A in musculoskeletal disorders are discussed, with the aim to provide a novel insight into their association.
| S-EPMC7493464 | biostudies-literature
Project description:Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.
| S-EPMC6778039 | biostudies-literature
Project description:Intramuscular fat (IMF) has a pivotal influence on meat quality, with its deposition being a multifaceted physiological interaction of several regulatory factors. N6-methyladenosine (m6A), the preeminent epigenetic alteration among eukaryotic RNA modifications, holds a crucial role in moderating post-transcriptional gene expression. However, there is a dearth of comprehensive understanding regarding the functional machinery of m6A modification in the context of IMF deposition in poultry. Our current study entails an analysis of the disparities in IMF within the breast and leg of 180-day-old Jingyuan chickens. We implemented methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to delve into the distribution of m6A and its putative regulatory frameworks on IMF deposition in chickens. The findings demonstrated a markedly higher IMF content in leg relative to breast (P < 0.01). Furthermore, the expression of METTL14, WTAP, FTO, and ALKBH5 was significantly diminished in comparison to that of breast (P < 0.01). The m6A peaks in the breast and leg primarily populated 3′untranslated regions (3′UTR) and coding sequence (CDS) regions. The leg, when juxtaposed with the breast, manifested 176 differentially methylated genes (DMGs), including 151 hyper-methylated DMGs and 25 hypo-methylated DMGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed a pronounced enrichment of DMGs in the biosynthesis of amino acids, peroxisome, Fatty acid biosynthesis, fatty acid elongation, and cell adhesion molecules (CAMs) pathways. Key DMGs, namely ECH1, BCAT1, and CYP1B1 were implicated in the regulation of muscle lipid anabolism. Our study offers substantial insight and forms a robust foundation for further exploration of the functional mechanisms of m6A modification in modulating IMF deposition. This holds profound theoretical importance for improving and leveraging meat quality in indigenous chicken breeds.
| S-EPMC10448335 | biostudies-literature
Project description:BACKGROUND:Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive. METHODS:Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation. FINDINGS:TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7. INTERPRETATION:Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. FUNDING:This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).
| S-EPMC7452680 | biostudies-literature
Project description:N6-Methyladenosine (m6A) RNA modification plays an essential role in many biological processes. To investigate the regulatory role of m6A on the skeletal muscle development in Hu sheep, this study took newborn Hu sheep (b_B Group) and six-month-old Hu sheep (s_B Group) as the objects. MeRIP-seq and RNA-Seq analysis techniques were used to detect differentially methylated genes (DMGs) and differentially expressed genes (DEGs) in the longissimus dorsi muscle of Hu sheep at different months of age. Then, conjoint analysis was further employed to screen for key genes involved in skeletal muscle development that are modified by m6A and expressed by mRNA. According to the results of the MeRIP-seq analysis, there were 285 m6A differentially methylated peaks (DMPs) in total between b_B Group and s_B Group, with 192 significant upregulated peaks and 93 significant downregulated peaks. GO and KEGG analysis revealed that DMGs are mainly enriched in actin-binding, cellular transport, and metabolic pathways. According to the results of the RNA-seq analysis, there were 4,349 DEGs in total between b_B Group and s_B Group, with 2010 upregulated genes and 2,339 downregulated genes. DEGs are found to be mainly enriched in the regulation of actin cytoskeleton tissue, AMPK and FoxO signaling pathways, etc. The conjoint analysis demonstrated that 283 genes were both modified by m6A and expressed by mRNA. Among them, three genes relevant to muscle growth (RGMB, MAPK8IP3, and RSPO3) were selected as candidates for quantitative validation, and the results were in line with the sequencing results. The results mentioned above all suggest that m6A plays a certain role in the skeletal muscle development in Hu sheep.
| S-EPMC11371687 | biostudies-literature
Project description:N6 -methyladenosine (m6 A) is the most prevalent internal modification present in mRNAs, and is considered to participate in a range of developmental and biological processes. Drought response is highly regulated at the genomic, transcriptional and post-transcriptional levels. However, the biological function and regulatory mechanism of m6 A modification in the drought stress response is still poorly understood. We generated a transcriptome-wide m6 A map using drought-resistant and drought-sensitive varieties of cotton under different water deficient conditions to uncover patterns of m6 A methylation in cotton response to drought stress. The results reveal that m6 A represents a common modification and exhibit dramatic changes in distribution during drought stress. More 5'UTR m6 A was deposited in the drought-resistant variety and was associated with a positive effect on drought resistance by regulating mRNA abundance. Interestingly, we observed that increased m6 A abundance was associated with increased mRNA abundance under drought, contributing to drought resistance, and vice versa. The demethylase GhALKBH10B was found to decrease m6 A levels, facilitating the mRNA decay of ABA signal-related genes (GhZEP, GhNCED4 and GhPP2CA) and Ca2+ signal-related genes (GhECA1, GhCNGC4, GhANN1 and GhCML13), and mutation of GhALKBH10B enhanced drought resistance at seedling stage in cotton. Virus-induced gene silencing (VIGS) of two Ca2+ -related genes, GhECA1 and GhCNGC4, reduced drought resistance with the decreased m6 A enrichment on silenced genes in cotton. Collectively, we reveal a novel mechanism of post-transcriptional modification involved in affecting drought response in cotton, by mediating m6 A methylation on targeted transcripts in the ABA and Ca2+ signalling transduction pathways.
| S-EPMC10214760 | biostudies-literature
Project description:N6 -methyladenosine (m6 A) RNA modification, first discovered in 1974, is the most prevalent, abundant and penetrating messenger RNA (mRNA) modification in eukaryotes. This governs the fate of modified transcripts, regulates RNA metabolism and biological processes, and participates in pathogenesis of numerous human diseases, especially in cancer through the reciprocal regulation of m6 A methyltransferases ("writers") and demethylases ("erasers") and the binding proteins decoding m6 A methylation ("readers"). Accumulating evidence indicates a complicated regulation network of m6 A modification involving multiple m6 A-associated regulatory proteins whose biological functions have been further analysed. This review aimed to summarize the current knowledge on the potential significance and molecular mechanisms of m6 A RNA modification in the initiation and progression of cancer.
| S-EPMC7653258 | biostudies-literature
Project description:N6-methyladenosine (m6A) constitutes one of the most abundant internal RNA modifications and is critical for RNA metabolism and function. It has been previously reported that viral RNA contains internal m6A modifications; however, only recently the function of m6A modification in viral RNAs has been elucidated during infections of HIV, hepatitis C virus and Zika virus. In the present study, we found that enterovirus 71 (EV71) RNA undergoes m6A modification during viral infection, which alters the expression and localization of the methyltransferase and demethylase of m6A, and its binding proteins. Moreover, knockdown of m6A methyltransferase resulted in decreased EV71 replication, whereas knockdown of the demethylase had the opposite effect. Further study showed that the m6A binding proteins also participate in the regulation of viral replication. In particular, two m6A modification sites were identified in the viral genome, of which mutations resulted in decreased virus replication, suggesting that m6A modification plays an important role in EV71 replication. Notably, we found that METTL3 interacted with viral RNA-dependent RNA polymerase 3D and induced enhanced sumoylation and ubiquitination of the 3D polymerase that boosted viral replication. Taken together, our findings demonstrated that the host m6A modification complex interacts with viral proteins to modulate EV71 replication.
| S-EPMC6326802 | biostudies-literature