GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy

Nat Commun. 2013:4:1830. doi: 10.1038/ncomms2823.

Abstract

Somatic hypermutation in B cells is initiated by activation-induced cytidine deaminase-catalyzed C→U deamination at immunoglobulin variable regions. Here we investigate the role of the germinal centre-associated nuclear protein (GANP) in enhancing the access of activation-induced cytidine deaminase (AID) to immunoglobulin variable regions. We show that the nuclear export factor GANP is involved in chromatin modification at rearranged immunoglobulin variable loci, and its activity requires a histone acetyltransferase domain. GANP interacts with the transcription stalling protein Spt5 and facilitates RNA Pol-II recruitment to immunoglobulin variable regions. Germinal centre B cells from ganp-transgenic mice showed a higher AID occupancy at the immunoglobulin variable region, whereas B cells from conditional ganp-knockout mice exhibit a lower AID accessibility. These findings suggest that GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acetyltransferases / metabolism*
  • Animals
  • B-Lymphocytes / metabolism
  • Cell Nucleus / metabolism
  • Cytidine Deaminase / metabolism*
  • DNA / metabolism
  • Down-Regulation / genetics
  • Gene Knockdown Techniques
  • Genetic Loci / genetics
  • Germinal Center / cytology
  • Histones / metabolism
  • Humans
  • Immunoglobulin Variable Region / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Nucleosomes / metabolism*
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Transcription, Genetic*

Substances

  • GANP protein, mouse
  • Histones
  • Immunoglobulin Variable Region
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Nucleosomes
  • Phosphoproteins
  • DNA
  • Acetyltransferases
  • MCM3AP protein, human
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase