METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m^(6)A methyltransferase complex(MTC)that installs m^(6)A.Surprisingly,depletion of METTL3 or METTL14 displayed distinct effects on ...METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m^(6)A methyltransferase complex(MTC)that installs m^(6)A.Surprisingly,depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell(mESC).While comparable global hypo-methylation in RNA m^(6)A was observed in Mettl3 or Mettl14 knockout mESCs,respectively.Mettl14 knockout led to a globally decreased nascent RNA synthesis,whereas Mettl3 depletion resulted in transcription upregulation,suggesting that METTL14 might possess an mA-independent role in gene regulation.We found that METTL14 colocalizes with the repressive H3K27me3 modification.Mechanistically,METTL14,but not METTL3,binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3.Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression.The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs.This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m^(6)A,and critically impacts transcriptional regulation,stemness maintenance,and differentiation ofmESCs.展开更多
基金supported by the National Institute of Health to C.H.(Nos.HG008935,ES030546,and R01ES030546)the National Natural Science Foundation of China to J.L.(No.32170595)+1 种基金the Beijing Nova Program to JL.(No.Z211100002121011)the Center for Life Sciences(CLS),the School of Life Sciences(SLS)of Peking University,the SLS-Qidong Innovation Fund,and the Li Ge Zhao Ning Life Science Junior Research Fellowship.C.H.is an investigator of the Howard Hughes Medical Institute.
文摘METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m^(6)A methyltransferase complex(MTC)that installs m^(6)A.Surprisingly,depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell(mESC).While comparable global hypo-methylation in RNA m^(6)A was observed in Mettl3 or Mettl14 knockout mESCs,respectively.Mettl14 knockout led to a globally decreased nascent RNA synthesis,whereas Mettl3 depletion resulted in transcription upregulation,suggesting that METTL14 might possess an mA-independent role in gene regulation.We found that METTL14 colocalizes with the repressive H3K27me3 modification.Mechanistically,METTL14,but not METTL3,binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3.Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression.The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs.This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m^(6)A,and critically impacts transcriptional regulation,stemness maintenance,and differentiation ofmESCs.
