title: Activation of terminal B cell differentiation by inhibition of histone deacetylation.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York, NY 14642, USA.
authors.forename: Sang C
authors.initials: SC
authors.lastname: Lee
authors.forename: Andrea
authors.initials: A
authors.lastname: Bottaro
authors.forename: Richard A
authors.initials: RA
authors.lastname: Insel
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007075:Immunoglobulin M / Q000378:metabolism; D051917:Leukosialin; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014176:Protein Biosynthesis; D011509:Proteoglycans / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D053668:Syndecan-1; D053667:Syndecans; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007075:Immunoglobulin M; D051917:Leukosialin; C499479:Mad protein, mouse; D008562:Membrane Glycoproteins; C513258:Prdm1 protein, mouse; D011509:Proteoglycans; D012097:Repressor Proteins; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D012795:Sialoglycoproteins; C497863:Spn protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D014157:Transcription Factors; C012589:trichostatin A; D000074462:Positive Regulatory Domain I-Binding Factor 1