GCN5 is essential for IRF-4 gene expression followed by transcriptional activation of Blimp-1 in immature B cells.
During B-cell differentiation, the gene expression of B-cell differentiation-related transcription factors must be strictly controlled by epigenetic mechanisms including histone acetylation and deacetylation, to complete the differentiation pathway. GCN5, one of the most important histone acetyltransferases, is involved in epigenetic events for transcriptional regulation through alterations in the chromatin structure. In this study, by analyzing the homozygous DT40 mutants GCN5(-/-), generated with gene targeting techniques, we found that GCN5 was necessary for transcriptional activation of IRF-4, an essential transcription factor for plasma cell differentiation. GCN5 deficiency caused drastic decreases in both the mRNA and the protein levels of Blimp-1 and IRF-4. The ectopic expression of Blimp-1 and IRF-4 suggests that IRF-4, but not Blimp-1, is the target gene of GCN5 in immature B cells. Moreover, a chromatin immunoprecipitation assay showed that GCN5 bound to the IRF-4 gene around its 5'-flanking region and acetylated H3K9 residues within chromatin surrounding the region in vivo, suggesting that gene expression of IRF-4 is certainly regulated by GCN5. These results reveal that GCN5 is essential for IRF-4 gene expression, followed by transcriptional activation of Blimp-1, and plays a key role in epigenetic regulation of B-cell differentiation.
1.Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200, Kihara, Kiyotake, Miyazaki 88-1692, Japan. masakari@med.miyazaki-u.ac.jp.
Hidehiko
H
Kikuchi
Masami
M
Nakayama
Futoshi
F
Kuribayashi
Shinobu
S
Imajoh-Ohmi
Hideki
H
Nishitoh
Yasunari
Y
Takami
Tatsuo
T
Nakayama
D000818:Animals; D030161:Avian Proteins / Q000096:biosynthesis / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000276:immunology*; D055786:Gene Knockout Techniques; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000276:immunology*; D015533:Transcriptional Activation / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics*; D000099218:Interferon Regulatory Factor-4
D030161:Avian Proteins; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; C435124:IRF4 protein, Gallus gallus; D000099218:Interferon Regulatory Factor-4
DT40; differentiation; epigenetics; gene targeting; histone acetyltransferase