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Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling.

Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation-linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.

Pubmed ID: 21131967


  • Levy D
  • Kuo AJ
  • Chang Y
  • Schaefer U
  • Kitson C
  • Cheung P
  • Espejo A
  • Zee BM
  • Liu CL
  • Tangsombatvisit S
  • Tennen RI
  • Kuo AY
  • Tanjing S
  • Cheung R
  • Chua KF
  • Utz PJ
  • Shi X
  • Prinjha RK
  • Lee K
  • Garcia BA
  • Bedford MT
  • Tarakhovsky A
  • Cheng X
  • Gozani O


Nature immunology

Publication Data

January 20, 2011

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA025800
  • Agency: NIAID NIH HHS, Id: F32AI080086
  • Agency: PHS HHS, Id: HHSN-268201999934C
  • Agency: NIA NIH HHS, Id: R01 AG028867
  • Agency: NIA NIH HHS, Id: R01 AG028867-05
  • Agency: NIGMS NIH HHS, Id: R01 GM079641
  • Agency: NIGMS NIH HHS, Id: R01 GM079641-04
  • Agency: NIDA NIH HHS, Id: R21 DA025800
  • Agency: NIDA NIH HHS, Id: R21 DA025800-01S1
  • Agency: NIDA NIH HHS, Id: R21 DA025800-02
  • Agency: NIAID NIH HHS, Id: T32 AI007290
  • Agency: NIAID NIH HHS, Id: U19-AI082719

Mesh Terms

  • Arthritis, Rheumatoid
  • Chromatin Assembly and Disassembly
  • DNA Methylation
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Humans
  • Inflammation
  • Lysine
  • NF-kappa B
  • Protein Binding
  • Protein Methyltransferases
  • RNA, Small Interfering
  • Signal Transduction
  • Transcription Factor RelA