BET proteins are a key component of immunoglobulin gene expression

Epigenomics. 2017 Apr;9(4):393-406. doi: 10.2217/epi-2016-0147. Epub 2017 Mar 21.

Abstract

Aim: BET proteins have been shown to regulate gene expression including inflammatory genes.

Methods: In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151).

Results: Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone-induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters.

Conclusion: Our results indicate that BET proteins including Brd4 play a crucial role regulation B-cell-specific gene expression and immunoglobulin production.

Keywords: B cells; Brd4; JQ1; Oct2; bromo and extraterminal domains; epigenetic gene regulation; histone modifications; immunoglobulin.

MeSH terms

  • Animals
  • Azepines / administration & dosage*
  • Azepines / pharmacology
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cell Cycle Proteins
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation / drug effects
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Immunoglobulin G / genetics*
  • Immunoglobulin G / metabolism
  • Mice
  • Nuclear Proteins / metabolism*
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2
  • Promoter Regions, Genetic / drug effects
  • Transcription Factors / metabolism*
  • Triazoles / administration & dosage*
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Immunoglobulin G
  • Nuclear Proteins
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Transcription Factors
  • Triazoles