Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40.
Modifications of histones are reportedly associated with the regulation of immunoglobulin (Ig) gene diversification mechanisms, but the extent of their involvement in promoting sequence alterations at the Ig variable (V) regions still remains to be elucidated. We have previously demonstrated that Ig gene conversion in the B cell line DT40 is accompanied by the local hyperacetylation of histones, and that its frequency is highly increased in cells treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA). In this report, we describe the enhancing effects of the homozygous deletion of HDAC2 (HDAC2-/-) on Ig gene conversion. Remarkably, sequence analysis revealed that the distribution of the gene conversion tracts induced throughout the Ig V regions in HDAC2-/- was significantly different from the diversification patterns in TSA-treated wild-type cultures. Furthermore, we found that the effects of HDAC2-/- and of the treatment with TSA were additive as regards histone acetylation, Ig gene transcription, gene conversion frequency and distribution of gene conversion tracts. These results underscore the potential participation of HDAC-mediated histone acetylation in Ig diversification, but also suggest a specific role of HDAC2 to control the spatial targeting of Ig gene conversion.
Lin
Waka
W
Shibata Distinguished Scientist Laboratory, RIKEN Discovery Research Institute, Saitama-ken, Japan.
Hashimoto
Shu-Ichi
S
Seo
Hidetaka
H
Shibata
Takehiko
T
Ohta
Kunihiro
K
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D005785:Gene Conversion / Q000187:drug effects / Q000235:genetics*; D017353:Gene Deletion; D005803:Genes, Immunoglobulin / Q000187:drug effects / Q000235:genetics*; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics*; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006720:Homozygote; D006877:Hydroxamic Acids / Q000494:pharmacology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000187:drug effects
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007135:Immunoglobulin Variable Region; D012097:Repressor Proteins; C012589:trichostatin A; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases