7SK methylation by METTL3 promotes transcriptional activity

Sci Adv. 2023 May 10;9(19):eade7500. doi: 10.1126/sciadv.ade7500. Epub 2023 May 10.

Abstract

A fundamental feature of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcriptional elongation by sequestering the cyclin dependent kinase 9/cyclin T1 (CDK9/CCNT1) positive transcription elongation factor (P-TEFb) complex. We found that epidermal growth factor signaling induces phosphorylation of the enzyme methyltransferase 3 (METTL3), leading to METTL3-mediated methylation of 7SK. 7SK methylation enhanced its binding to heterogeneous nuclear ribonucleoproteins, causing the release of the HEXIM1 P-TEFb complex subunit1 (HEXIM1)/P-TEFb complex and inducing transcriptional elongation. Our findings establish the mechanism underlying 7SK activation and uncover a previously unknown function for the m6A modification in converting growth factor signaling events into a regulatory transcriptional response via an RNA methylation-dependent switch.

MeSH terms

  • Humans
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Positive Transcriptional Elongation Factor B* / genetics
  • Positive Transcriptional Elongation Factor B* / metabolism
  • RNA, Small Nuclear / genetics
  • RNA, Small Nuclear / metabolism
  • RNA-Binding Proteins* / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • HEXIM1 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Positive Transcriptional Elongation Factor B
  • RNA, Small Nuclear
  • RNA-Binding Proteins
  • Transcription Factors