Role of lysine methylation of NF-?B in differential gene regulation

Tao Lu, Maojing Yang, De Bin Huang, Han Wei, Gulcin H. Ozer, Gourisankar Ghosh, George R. Stark

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Lysine methylation of the p65 subunit of nuclear factor ?B (NF-?B) on K218 and K221 together or K37 alone strongly enhances gene expression in response to cytokines. We analyzed the effects of Kto-Q mutations in the REL homology domain of p65 on the response to IL-1? in 293 cells with low levels of p65. The K218/221Q mutation greatly reduced the expression of 39 of 82 genes, whereas the K37Q mutation reduced the expression of 23 different genes. Enhanced expression of the lysine demethylase FBXL11, which catalyzes the demethylation of K218 and K221 specifically, inhibited the expression of most of the genes that were inhibited by the DKQ mutation. CHIP-Seq analysis showed that the K218/221Q mutation greatly reduces the affinity of p65 for many promoters and that the K37Q mutation does not. Structural modeling showed that the newly introduced methyl groups of K218 and K221 interact directly with DNA to increase the affinity of p65 for specific ?B sites. Thus, the K218/221Q and K37Q mutations have dramatically different effects because methylations of these residues affect different genes by distinct mechanisms.

Original languageEnglish (US)
Pages (from-to)13510-13515
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number33
DOIs
StatePublished - Aug 13 2013

Keywords

  • Histone modifying enzyme
  • Protein methylation

ASJC Scopus subject areas

  • General

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