Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription.
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.
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
Minna U
MU
Kaikkonen
Nathanael J
NJ
Spann
Sven
S
Heinz
Casey E
CE
Romanoski
Karmel A
KA
Allison
Joshua D
JD
Stender
Hyun B
HB
Chun
David F
DF
Tough
Rab K
RK
Prinjha
Christopher
C
Benner
Christopher K
CK
Glass
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1; D004268:DNA-Binding Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D051788:Myeloid-Lymphoid Leukemia Protein; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000099232:Proto-Oncogene Protein Spi-1; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; C497423:Kmt2a protein, mouse; C510860:Kmt2d protein, mouse; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins; C516439:MLL4 protein, mouse