Determinants of a transcriptionally competent environment at the GM-CSF promoter.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is produced by T cells, but not B cells, in response to immune signals. GM-CSF gene activation in response to T-cell stimulation requires remodelling of chromatin associated with the gene promoter, and these changes do not occur in B cells. While the CpG methylation status of the murine GM-CSF promoter shows no correlation with the ability of the gene to respond to activation, we find that the basal chromatin environment of the gene promoter influences its ability to respond to immune signals. In unstimulated T cells but not B cells, the GM-CSF promoter is selectively marked by enrichment of histone acetylation, and association of the chromatin-remodelling protein BRG1. BRG1 is removed from the promoter upon activation concomitant with histone depletion and BRG1 is required for efficient chromatin remodelling and transcription. Increasing histone acetylation at the promoter in T cells is paralleled by increased BRG1 recruitment, resulting in more rapid chromatin remodelling, and an associated increase in GM-CSF mRNA levels. Furthermore, increasing histone acetylation in B cells removes the block in chromatin remodelling and transcriptional activation of the GM-CSF gene. These data are consistent with a model in which histone hyperacetylation and BRG1 enrichment at the GM-CSF promoter, generate a chromatin environment competent to respond to immune signals resulting in gene activation.
Brettingham-Moore
K H
KH
Menzies Research Institute, University of Tasmania, Private Bag 58, Hobart 7001, Tasmania, Australia.
Sprod
O R
OR
Chen
X
X
Oakford
P
P
Shannon
M F
MF
Holloway
A F
AF
D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands; D004265:DNA Helicases / Q000032:analysis; D019175:DNA Methylation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000032:analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000032:analysis; D015533:Transcriptional Activation
D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C513194:Smarca4 protein, mouse; D004265:DNA Helicases