Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription.

TitleChromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription.
Publication TypeJournal Article
Year of Publication2016
AuthorsJosefowicz SZ, Shimada M, Armache A, Li CH, Miller RM, Lin S, Yang A, Dill BD, Molina H, Park H-S, Garcia BA, Taunton J, Roeder RG, C Allis D
JournalMol Cell
Date Published2016 10 20
KeywordsBacterial Proteins, Cell Cycle Proteins, Cell Line, Tumor, Chromatin, Epithelial Cells, Feedback, Physiological, HeLa Cells, Histones, Humans, Kinetics, Luminescent Proteins, Mitosis, Models, Statistical, Molecular Imaging, Recombinant Fusion Proteins, Time Factors, Transcription Factors, Transcription, Genetic

The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen- and stress-activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription.

Alternate JournalMol Cell
PubMed ID27768872
PubMed Central IDPMC5081221
Grant ListR01 GM040922 / GM / NIGMS NIH HHS / United States
R01 DK071900 / DK / NIDDK NIH HHS / United States
R01 CA129325 / CA / NCI NIH HHS / United States
K99 GM113019 / GM / NIGMS NIH HHS / United States
R01 AI118891 / AI / NIAID NIH HHS / United States
R01 GM110174 / GM / NIGMS NIH HHS / United States
Related Faculty: 
Steven Josefowicz, Ph.D.

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