Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.
|Title||Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Kaikkonen MU, Spann NJ, Heinz S, Romanoski CE, Allison KA, Stender JD, Chun HB, Tough DF, Prinjha RK, Benner C, Glass CK|
|Date Published||2013 Aug 8|
|Keywords||Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, DNA Methylation, Enhancer Elements, Genetic, Gene Expression, Gene Expression Regulation, Histone-Lysine N-Methyltransferase, Histones, Macrophage Activation, Macrophages, Male, Mice, Mice, Inbred C57BL, Myeloid-Lymphoid Leukemia Protein, NF-kappa B, Proto-Oncogene Proteins, RNA Polymerase II, Sequence Analysis, DNA, Signal Transduction, Toll-Like Receptor 4, Trans-Activators, Transcription Factor RelA, Transcription, Genetic|
Recent studies suggest a hierarchical model in which lineage-determining factors act in a collaborative manner to select and prime cell-specific enhancers, thereby enabling signal-dependent transcription factors to bind and function in a cell-type-specific manner. Consistent with this model, TLR4 signaling primarily regulates macrophage gene expression through a pre-existing enhancer landscape. However, TLR4 signaling also induces priming of ∼3,000 enhancer-like regions de novo, enabling visualization of intermediates in enhancer selection and activation. Unexpectedly, we find that enhancer transcription precedes local mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). H3K4 methylation at de novo enhancers is primarily dependent on the histone methyltransferases Mll1, Mll2/4, and Mll3 and is significantly reduced by inhibition of RNA polymerase II elongation. Collectively, these findings suggest an essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts.
|Alternate Title||Mol. Cell|