Epigenetic regulation of autophagy by the methyltransferase G9a

Amaia Artal Martinez De Narvajas, Timothy S. Gomez, Jin San Zhang, Alexander O. Mann, Yoshiyuki Taoda, Jacquelyn A. Gorman, Marta Herreros-Villanueva, Thomas M. Gress, Volker Ellenrieder, Luis Bujand, Do Hyung Kim, Alan P. Kozikowski, Alexander Koenig, Daniel D. Billadeau

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.

Original languageEnglish (US)
Pages (from-to)3983-3993
Number of pages11
JournalMolecular and cellular biology
Issue number20
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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