title: Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription.
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.
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: steven.josefowicz@rockefeller.edu.
authors: Steven Z
authors: SZ
authors: Josefowicz
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors: Miho
authors: M
authors: Shimada
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors: Anja
authors: A
authors: Armache
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors: Charles H
authors: CH
authors: Li
authors: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Rand M
authors: RM
authors: Miller
authors: Epigenetics Program, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Shu
authors: S
authors: Lin
authors: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors: Aerin
authors: A
authors: Yang
authors: Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
authors: Brian D
authors: BD
authors: Dill
authors: Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
authors: Henrik
authors: H
authors: Molina
authors: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors: Hee-Sung
authors: HS
authors: Park
authors: Epigenetics Program, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Benjamin A
authors: BA
authors: Garcia
authors: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Jack
authors: J
authors: Taunton
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: robert.roeder@rockefeller.edu.
authors: Robert G
authors: RG
authors: Roeder
authors: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: c.david.allis@rockefeller.edu.
authors: C David
authors: CD
authors: Allis
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D025461:Feedback, Physiological; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D015233:Models, Statistical; D057054:Molecular Imaging; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000097573:Red Fluorescent Protein; C054562:yellow fluorescent protein, Bacteria
keywords: H3S28ph; chromatin; epigenetics; histone phosphorylation; inflammation; macrophage; mitogen- and stress-activated protein kinase (MSK); p300; transcription