RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological func...RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA （mRNA）, such as NT-methylguanosine （mVG） at the cap, Nr-methyl-2＇-O-methyladenosine （m6Am）, 2＇-O-methylation （Nm） within the cap and the internal positions, and internal N6-methyladenosine （m6A） and 5-methylcytosine （mSC）. Among them, mTG cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export, m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. mrA has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein （FRO） and its homolog protein, alkylation repair ho- molog 5 （ALKBH5）. b-TO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states： N6-hydroxymethyladenosine （hm6A） and Nr-formyladenosine （frA）. The two newly discovered m6A demethylases, bTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible mrA, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field ＂RNA Epige- netics＂. 5-methylcytosine （5mC） as an epigenetic mark in DNA has been studied widely, but mSC in mRNA is seldom explored. The bisulfide sequencing showed mSC is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future 19erspectives on functional studies.展开更多
Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in thi...Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in this process,their roles in head and neck squamous cell carcinoma(HNSCC)remain largely unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G methyltransferase complex components Methyltransferase-like 1(METTL1)/WD repeat domain 4(WDR4)were upregulated in HNSCC and associated with a poor prognosis.Functionally,METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models.Mechanistically,ablation of METTL1 reduced the m'G levels of 16 tRNAS,inhibiting the translation of a subset of oncogenic transcripts,including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)signaling pathway.In addition,chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI was found to promote the development and malignancy of HNSCC through regulating global mRNA translation,including the PI3K/AKT/mTOR signaling pathway,and found to alter immune landscape.METTLI could be a promising treatment target for HNSCC patients.展开更多
Among over 170 different types of chemical modifications on RNA nucleobases identified so far,RNA methylation is the major type of epitranscriptomic modifications existing on almost all types of RNAs,and has been demo...Among over 170 different types of chemical modifications on RNA nucleobases identified so far,RNA methylation is the major type of epitranscriptomic modifications existing on almost all types of RNAs,and has been demonstrated to participate in the entire process of RNA metabolism,including transcription,pre-mRNA alternative splicing and maturation,mRNA nucleus export,mRNA degradation and stabilization,mRNA translation.Attributing to the development of high-throughput detection technologies and the identification of both dynamic regulators and recognition proteins,mechanisms of RNA methylation modification in regulating the normal development of the organism as well as various disease occurrence and developmental abnormalities upon RNA methylation dysregulation have become increasingly clear.Here,we particularly focus on three types of RNA methylations:N^(6)-methylcytosine(m^(6)A),5-methylcytosine(m^(5)C),and N^(7)-methyladenosine(m^(7)G).We summarize the elements related to their dynamic installment and removal,specific binding proteins,and the development of high-throughput detection technologies.Then,for a comprehensive understanding of their biological significance,we also overview the latest knowledge on the underlying mechanisms and key roles of these three mRNA methylation modifications in gametogenesis,embryonic development,immune system development,as well as disease and tumor progression.展开更多
基金supported by the grant from the National Natural Science Foundation of China (No. 21210003)
文摘RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA （mRNA）, such as NT-methylguanosine （mVG） at the cap, Nr-methyl-2＇-O-methyladenosine （m6Am）, 2＇-O-methylation （Nm） within the cap and the internal positions, and internal N6-methyladenosine （m6A） and 5-methylcytosine （mSC）. Among them, mTG cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export, m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. mrA has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein （FRO） and its homolog protein, alkylation repair ho- molog 5 （ALKBH5）. b-TO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states： N6-hydroxymethyladenosine （hm6A） and Nr-formyladenosine （frA）. The two newly discovered m6A demethylases, bTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible mrA, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field ＂RNA Epige- netics＂. 5-methylcytosine （5mC） as an epigenetic mark in DNA has been studied widely, but mSC in mRNA is seldom explored. The bisulfide sequencing showed mSC is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future 19erspectives on functional studies.
基金National Natural Science Foundation of China,Grant/Award Numbers:81872409,82173362Natural Science Foundation of Guangdong Province,Grant/Award Numbers:2018A030313610,2019A1515110110,2020A1515010291+1 种基金The Open Funding of the State Key Laboratory of Oral Diseases,Grant/Award Number:SKLOD2021OF02and the use was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-Sen University(2016074).The nude mouse experi-ments performed were approved by the Laboratory Ani-mal Center of Sun Yat-SenUniversity(SYSU-IACUC-2021-000092).The transgenic mouse experiments performed were approved by the Laboratory Animal Center of Sun Yat-Sen University(SYSU-IACUC-2020-000569).
文摘Background:Cancer cells selectively promote the translation of oncogenic tran-scripts to stimulate cancer progression.Although growing evidence has revealed that tRNA modifications and related genes participate in this process,their roles in head and neck squamous cell carcinoma(HNSCC)remain largely unchar-acterized.Here,we sought to investigate the function and mechanisms of the transfer RNA(tRNA)N7-methylguanosine(m'G)modification in regulating the occurrence and development of HNSCC.Methods:Cell lost of-function and gain-of function assays,xenograft models,conditional knockout and knockin mouse models were used to study the physi-ological functions of tRNA m'G modification in HNSCC tumorigenesis.tRNA modification and expression profiling,mRNA translation profiling and res-cue assays were performed to uncover the underlying molecular mechanisms.Single-cell RNA sequencing(scRNA seq)was conducted to explore the tumor microenvironment changes.Results:The tRNA.m7G methyltransferase complex components Methyltransferase-like 1(METTL1)/WD repeat domain 4(WDR4)were upregulated in HNSCC and associated with a poor prognosis.Functionally,METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models.Mechanistically,ablation of METTL1 reduced the m'G levels of 16 tRNAS,inhibiting the translation of a subset of oncogenic transcripts,including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)signaling pathway.In addition,chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettll in mouse HNSCC.Furthermore,scRNA-seq results revealed that Mettll knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment.Conclusions:The tRNA m?G methyltransferase METTLI was found to promote the development and malignancy of HNSCC through regulating global mRNA translation,including the PI3K/AKT/mTOR signaling pathway,and found to alter immune landscape.METTLI could be a promising treatment target for HNSCC patients.
基金supported by the National Natural Science Foundation of China(32121001,32201213)。
文摘Among over 170 different types of chemical modifications on RNA nucleobases identified so far,RNA methylation is the major type of epitranscriptomic modifications existing on almost all types of RNAs,and has been demonstrated to participate in the entire process of RNA metabolism,including transcription,pre-mRNA alternative splicing and maturation,mRNA nucleus export,mRNA degradation and stabilization,mRNA translation.Attributing to the development of high-throughput detection technologies and the identification of both dynamic regulators and recognition proteins,mechanisms of RNA methylation modification in regulating the normal development of the organism as well as various disease occurrence and developmental abnormalities upon RNA methylation dysregulation have become increasingly clear.Here,we particularly focus on three types of RNA methylations:N^(6)-methylcytosine(m^(6)A),5-methylcytosine(m^(5)C),and N^(7)-methyladenosine(m^(7)G).We summarize the elements related to their dynamic installment and removal,specific binding proteins,and the development of high-throughput detection technologies.Then,for a comprehensive understanding of their biological significance,we also overview the latest knowledge on the underlying mechanisms and key roles of these three mRNA methylation modifications in gametogenesis,embryonic development,immune system development,as well as disease and tumor progression.
