TY - JOUR
T1 - Epigenetic regulation of autophagy by the methyltransferase G9a
AU - De Narvajas, Amaia Artal Martinez
AU - Gomez, Timothy S.
AU - Zhang, Jin San
AU - Mann, Alexander O.
AU - Taoda, Yoshiyuki
AU - Gorman, Jacquelyn A.
AU - Herreros-Villanueva, Marta
AU - Gress, Thomas M.
AU - Ellenrieder, Volker
AU - Bujand, Luis
AU - Kim, Do Hyung
AU - Kozikowski, Alan P.
AU - Koenig, Alexander
AU - Billadeau, Daniel D.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.00813-13
DO - 10.1128/MCB.00813-13
M3 - Article
C2 - 23918802
AN - SCOPUS:84886920194
SN - 0270-7306
VL - 33
SP - 3983
EP - 3993
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 20
ER -