Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression

Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16321-6. doi: 10.1073/pnas.0505045102. Epub 2005 Oct 27.

Abstract

Class II major histocompatibility (MHC-II) genes are prototype targets of IFN-gamma. IFN-gamma activates the expression of the non-DNA-binding master regulator of MHC-II, class II transactivator (CIITA), which is crucial for enhanceosome formation and gene activation. This report shows the importance of the histone methyltransferase, coactivator-associated arginine methyltransferase (CARM1/PRMT4), during IFN-gamma-induced MHC-II gene activation. It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process. CARM1 synergizes with CIITA in activating MHC-II transcription and synergy is abrogated when an arginine methyltransferase-defective CARM1 mutant is used. Protein-arginine methyltransferase 1 has much less effect on MHC-II transcription. Specific RNA interference reduced CARM1 expression as well as MHC-II expression. The recruitment of CARM1 to the promoter requires endogenous CIITA and results in methylation of histone H3-R17; hence, CIITA is an upstream regulator of histone methylation. Previous work has shown that CARM1 can methylate CBP at three arginine residues. Using wild-type CBP and a mutant of CBP lacking the CARM1-targeted arginine residues (R3A), we show that arginine methylation of CBP is required for IFN-gamma induction of MHC-II. A kinetic analysis shows that CIITA, CARM1, and H3-R17 methylation all precede CBP loading on the MHC-II promoter during IFN-gamma treatment. These results suggest functional and temporal relationships among CIITA, CARM1, and CBP for IFN-gamma induction of MHC-II.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / physiology*
  • Cell Line
  • Corticosterone
  • Gene Expression Regulation / drug effects*
  • Genes, MHC Class II*
  • HLA-DR Antigens / genetics
  • HLA-DR alpha-Chains
  • Humans
  • Interferon-gamma / pharmacology*
  • Methylation
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic
  • Protein-Arginine N-Methyltransferases / physiology*
  • RNA, Small Interfering / pharmacology
  • Trans-Activators / physiology*
  • Transcription, Genetic
  • Transcriptional Activation

Substances

  • Carrier Proteins
  • HLA-DR Antigens
  • HLA-DR alpha-Chains
  • MHC class II transactivator protein
  • Nuclear Proteins
  • RNA, Small Interfering
  • Trans-Activators
  • Interferon-gamma
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • Corticosterone