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Mol Cell. 2016 Oct 20;64(2):347-361. doi: 10.1016/j.molcel.2016.09.026.

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

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: steven.josefowicz@rockefeller.edu.
2
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
3
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
4
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
5
Epigenetics Program, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
7
Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
8
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: robert.roeder@rockefeller.edu.
9
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: c.david.allis@rockefeller.edu.

Abstract

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.

KEYWORDS:

H3S28ph; chromatin; epigenetics; histone phosphorylation; inflammation; macrophage; mitogen- and stress-activated protein kinase (MSK); p300; transcription

PMID:
27768872
PMCID:
PMC5081221
DOI:
10.1016/j.molcel.2016.09.026
[Indexed for MEDLINE]
Free PMC Article

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