Activation of terminal B cell differentiation by inhibition of histone deacetylation

Mol Immunol. 2003 May;39(15):923-32. doi: 10.1016/s0161-5890(03)00029-4.

Abstract

A role for histone acetylation, which can alter the accessibility of DNA to transcriptional regulatory proteins and contribute to gene expression, in regulating terminal B cell differentiation was investigated in the mature B lymphoma L10A and mouse splenic B cells. Incubation of the L10A cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and butyrate increased expression of Blimp-1, J chain, and mad genes, decreased expression of c-myc and BSAP/Pax-5 genes, increased the expression of surface CD43 and Syndecan-1, and decreased surface IgM. Incubation of splenic B cells with TSA and dextran conjugated anti-IgD Ab increased Blimp-1 gene and Syndecan-1 surface expression. The alteration in gene expression and cell surface markers was consistent with induction of the onset of terminal B cell differentiation. Co-incubation of L10A cells with TSA and cycloheximide (CHX) abrogated the up-regulation of Blimp-1 expression, indicating that TSA-activated Blimp-1 expression required synthesis of a transcriptional activator. In contrast, mad expression was increased in L10A cells cultured with TSA and cycloheximide or cycloheximide alone, suggesting mad expression may occur independent of Blimp-1 expression and is regulated by a labile, HDAC associated transcriptional repressor. The results demonstrate that histone acetylation regulates transcription of genes controlling terminal B cell differentiation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Histone Deacetylase Inhibitors*
  • Hydroxamic Acids / pharmacology
  • Immunoglobulin M / metabolism
  • Leukosialin
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein Biosynthesis
  • Proteoglycans / biosynthesis
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Sialoglycoproteins / biosynthesis
  • Spleen / immunology
  • Syndecan-1
  • Syndecans
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Immunoglobulin M
  • Leukosialin
  • Mad protein, mouse
  • Membrane Glycoproteins
  • Prdm1 protein, mouse
  • Proteoglycans
  • Repressor Proteins
  • SDC1 protein, human
  • Sdc1 protein, mouse
  • Sialoglycoproteins
  • Spn protein, mouse
  • Syndecan-1
  • Syndecans
  • Transcription Factors
  • trichostatin A
  • Positive Regulatory Domain I-Binding Factor 1