Open AccessMechanism of Action of a Distal NF-κB-Dependent Enhancer
Author(s) -
Belete Teferedegne,
Myesha R. Green,
Zhu Guo,
Jeremy M. Boss
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00271-06
Subject(s) - enhancer , biology , coactivator , transcription factor , chromatin , histone , p300 cbp transcription factors , regulation of gene expression , microbiology and biotechnology , promoter , transcription (linguistics) , sp1 transcription factor , gene expression , gene , genetics , linguistics , philosophy , histone acetyltransferases
The monocyte chemoattractant protein 1 gene (MCP -1 ) is regulated by TNF through an NF-κB-dependent distal enhancer and an Sp1-dependent promoter-proximal regulatory region. In the silent state, only the distal regulatory region is accessible to transcription factors. Upon activation by tumor necrosis factor, NF-κB binds to the distal regulatory region and recruits CBP and p300. CBP and p300 recruitment led to specific histone modifications that ultimately enabled the binding of Sp1 to the proximal regulatory region. During this process, a direct interaction between the distal and proximal regulatory regions occurred. Sp1, NF-κB, CBP, and p300 were required for this interaction. CBP/p300-mediated histone modifications enhanced the binding of the coactivator CARM1 to the distal regulatory region. CARM1, which is necessary forMCP -1 expression, was not required for distal-proximal region interactions, suggesting that it plays a later downstream activation event. The results describe a model in which the separation of the distal enhancer from the promoter-proximal region allows for two independent chromatin states to exist, preventing inappropriate gene activation at the promoter while at the same time allowing rapid induction through the distal regulatory region.