N6-甲基腺嘌呤(N6-methyladenosine,m6A)是真核生物信使RNA中最普遍的一种修饰。Wilms肿瘤蛋白1相关蛋白(Wilms'tumor 1-associating protein,WTAP)作为m6A甲基化转移酶的调控亚基,与甲基转移样蛋白3(methyltransferase-like protei...N6-甲基腺嘌呤(N6-methyladenosine,m6A)是真核生物信使RNA中最普遍的一种修饰。Wilms肿瘤蛋白1相关蛋白(Wilms'tumor 1-associating protein,WTAP)作为m6A甲基化转移酶的调控亚基,与甲基转移样蛋白3(methyltransferase-like protein 3,METTL3)、甲基转移样蛋白14(methyltransferase-like protein 14,METTL14)组成WMM复合物,催化m6A的产生。大量证据表明,WTAP可以通过调控RNA代谢,影响肿瘤的发生和进展,并与肿瘤的预后有着显著的相关性。本篇综述将关注WTAP的生物学功能和肿瘤中的作用,以及其作为肿瘤治疗潜在靶点的可行性。展开更多
N^(6)-methyladenosine(m^(6)A)modification,which is achieved by the METTL3/METTL14/WTAP methyltransferase complex,is the most abundant internal mRNA modification.Although recent evidence indicates that m^(6)A can regul...N^(6)-methyladenosine(m^(6)A)modification,which is achieved by the METTL3/METTL14/WTAP methyltransferase complex,is the most abundant internal mRNA modification.Although recent evidence indicates that m^(6)A can regulate neurodevelopment as well as synaptic function,the roles of m^(6)A modification in the cerebellum and related synaptic connections are not well established.Here,we report that Purkinje cell(PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death.Loss of Wtap also causes the aberrant degradation of multiple PC synapses.WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m^(6)A methylation in PCs.Moreover,the expression of GFAP and NF-L in the degenerating cerebellum is increased,suggesting severe neuronal injuries.In conclusion,this study demonstrates the critical role of WTAP-mediated m^(6)A modification in cerebellar PCs,thus providing unique insights related to neurodegenerative disorders.展开更多
Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular...Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular mechanisms that determine the maturation of brown adipocytes during postnatal development are not fully understood.Here,we identify Wilms’tumor 1-associating protein(WTAP)as an essential regulator in the postnatal development and maturation of BAT.BAT-specific knockout of Wtap(Wtap-BKO)severely impairs maturation of BAT in vivo by decreasing the expression of BAT-selective genes,leading to the whitening of interscapular BAT(iBAT).Single nucleus RNA-sequencing analysis shows the dynamic changes of cell heterogeneity in iBAT of Wtap-BKO mice.Adult mice with WTAP deficiency in BAT display hypothermic and succumb to acute cold challenge.Mechanistically,WTAP deficiency decreases m6A mRNA modification by reducing the protein stability of METTL3.BAT-specific overexpression of Mettl3 partially rescues the phenotypes observed in Wtap-BKO mice.These data demonstrate that WTAP/METTL3 plays an essential role in iBAT postnatal development and thermogenesis.展开更多
弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是非霍奇金淋巴瘤(non-hodgkin lymphoma,NHL)中最常见的亚型,其发病机制错综复杂,至今尚未被充分阐明。因其具有较大的异质性导致患者预后差,针对DLBCL的治疗面临着巨大的挑战...弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是非霍奇金淋巴瘤(non-hodgkin lymphoma,NHL)中最常见的亚型,其发病机制错综复杂,至今尚未被充分阐明。因其具有较大的异质性导致患者预后差,针对DLBCL的治疗面临着巨大的挑战。近年来,表观遗传修饰成为DLBCL发病机制的研究热点。越来越多的研究表明,m6A-RNA甲基化可动态调节DLBCL的发生发展。该文就m6A-RNA甲基化修饰在DLBCL中的研究进展作一综述,从表观遗传学的角度为DLBCL的早期诊断、治疗以及预后提供新策略。展开更多
The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs....The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m^(6)A modifications.Our findings provide functional insight into the correlation between circHECW2 and m^(6)A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.展开更多
文摘N6-甲基腺嘌呤(N6-methyladenosine,m6A)是真核生物信使RNA中最普遍的一种修饰。Wilms肿瘤蛋白1相关蛋白(Wilms'tumor 1-associating protein,WTAP)作为m6A甲基化转移酶的调控亚基,与甲基转移样蛋白3(methyltransferase-like protein 3,METTL3)、甲基转移样蛋白14(methyltransferase-like protein 14,METTL14)组成WMM复合物,催化m6A的产生。大量证据表明,WTAP可以通过调控RNA代谢,影响肿瘤的发生和进展,并与肿瘤的预后有着显著的相关性。本篇综述将关注WTAP的生物学功能和肿瘤中的作用,以及其作为肿瘤治疗潜在靶点的可行性。
基金supported by the National Natural Science Foundation of China(82121003,81970841,and 81790643)the Department of Science and Technology of Sichuan Province(2021YFS0386,2021YFS0369,20ZYD038,20ZYD037,2020JDZH0026,2021JDZH0022)+2 种基金the CAMS Innovation Fund for Medical Sciences(2019-12M-5-032)Huanhua Distingished Scholar grantthe Department of Chengdu Science and Technology(2021-YF05-01316-SN)。
文摘N^(6)-methyladenosine(m^(6)A)modification,which is achieved by the METTL3/METTL14/WTAP methyltransferase complex,is the most abundant internal mRNA modification.Although recent evidence indicates that m^(6)A can regulate neurodevelopment as well as synaptic function,the roles of m^(6)A modification in the cerebellum and related synaptic connections are not well established.Here,we report that Purkinje cell(PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death.Loss of Wtap also causes the aberrant degradation of multiple PC synapses.WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m^(6)A methylation in PCs.Moreover,the expression of GFAP and NF-L in the degenerating cerebellum is increased,suggesting severe neuronal injuries.In conclusion,this study demonstrates the critical role of WTAP-mediated m^(6)A modification in cerebellar PCs,thus providing unique insights related to neurodegenerative disorders.
基金This study was supported by the National Natural Science Foundation of China grant(92057110,31971083,92057115,and 32071138)National Key R&D Program of China(2020YFA0803800,2019YFA0801900,2020YFA0803601,and 2018YFA0801300).
文摘Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular mechanisms that determine the maturation of brown adipocytes during postnatal development are not fully understood.Here,we identify Wilms’tumor 1-associating protein(WTAP)as an essential regulator in the postnatal development and maturation of BAT.BAT-specific knockout of Wtap(Wtap-BKO)severely impairs maturation of BAT in vivo by decreasing the expression of BAT-selective genes,leading to the whitening of interscapular BAT(iBAT).Single nucleus RNA-sequencing analysis shows the dynamic changes of cell heterogeneity in iBAT of Wtap-BKO mice.Adult mice with WTAP deficiency in BAT display hypothermic and succumb to acute cold challenge.Mechanistically,WTAP deficiency decreases m6A mRNA modification by reducing the protein stability of METTL3.BAT-specific overexpression of Mettl3 partially rescues the phenotypes observed in Wtap-BKO mice.These data demonstrate that WTAP/METTL3 plays an essential role in iBAT postnatal development and thermogenesis.
文摘弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)是非霍奇金淋巴瘤(non-hodgkin lymphoma,NHL)中最常见的亚型,其发病机制错综复杂,至今尚未被充分阐明。因其具有较大的异质性导致患者预后差,针对DLBCL的治疗面临着巨大的挑战。近年来,表观遗传修饰成为DLBCL发病机制的研究热点。越来越多的研究表明,m6A-RNA甲基化可动态调节DLBCL的发生发展。该文就m6A-RNA甲基化修饰在DLBCL中的研究进展作一综述,从表观遗传学的角度为DLBCL的早期诊断、治疗以及预后提供新策略。
基金This work was supported by grants from the Science and Technology Innovation 2030-Major Project of the Ministry of Science and Technology of China(2021ZD0202904/2021ZD0202900)the National Science Fund Distinguished Young Scholars(82025033,China)+4 种基金the National Natural Science Foundation of China(82230115,82273914,81903591,82372024,82003733)the Natural Science Foundation of Jiangsu Province(BK20200358,China)ZhiShan Scholar Program of Southeast University(2242022R40059 and 2242021R40023,China)the Jiangsu Provincial Key Laboratory of Critical Care Medicine(JSKLCCM-2022-02-008,China)the Open Project Program of the Key Laboratory of Developmental Genes and Human Diseases of the Ministry of Education(LDGHD202304,China).
文摘The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m^(6)A modifications.Our findings provide functional insight into the correlation between circHECW2 and m^(6)A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.
