SOX4-mediated repression of specific tRNAs inhibits proliferation of human glioblastoma cells

Jianjing Yang, Derek K. Smith, Haoqi Ni, Ke Wu, Dongdong Huang, Sishi Pan, Adwait A. Sathe, Yu Tang, Meng Lu Liu, Chao Xing, Chun Li Zhang, Qichuan Zhuge

Research output: Contribution to journalArticle

Abstract

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAiMet. Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAiMet greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAiMet partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

Original languageEnglish (US)
Pages (from-to)5782-5790
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number11
DOIs
StatePublished - Mar 17 2020

Keywords

  • Glioblastoma
  • MRNA translation
  • SOX4
  • TRNA expression
  • TRNAi

ASJC Scopus subject areas

  • General

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