TY - JOUR
T1 - Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation
AU - Muneer, Adil
AU - Wang, Li
AU - Xie, Ling
AU - Zhang, Feng
AU - Wu, Bing
AU - Mei, Liu
AU - Lenarcic, Erik M.
AU - Feng, Emerald Hillary
AU - Song, Juan
AU - Xiong, Yan
AU - Yu, Xufen
AU - Wang, Charles
AU - Jain, Kanishk
AU - Strahl, Brian D.
AU - Cook, Jeanette Gowen
AU - Wan, Yisong Y.
AU - Moorman, Nathaniel John
AU - Song, Hongjun
AU - Jin, Jian
AU - Chen, Xian
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/12/21
Y1 - 2023/12/21
N2 - We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous “G9a-translated” proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
AB - We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous “G9a-translated” proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
KW - ARDS
KW - COVID-19
KW - T cell impairment
KW - acute respiratory distress syndrome
KW - endotoxin tolerance
KW - hyperinflammation
KW - protein-specific translation mechanism
KW - regulation of chronic inflammation
KW - sepsis
KW - translation-targeted medication
KW - translational function of an epigenetic regulator
UR - http://www.scopus.com/inward/record.url?scp=85176379929&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2023.09.012
DO - 10.1016/j.chembiol.2023.09.012
M3 - Article
C2 - 37858336
AN - SCOPUS:85176379929
SN - 2451-9448
VL - 30
SP - 1525-1541.e7
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 12
ER -