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Signaling to histone H3 for augmented transcription in the inflammatory response

ABSTRACT: The inflammatory response depends upon selective, rapid transcription initiation and high-level generation of gene products for defense against pathogens and environmental insult1,2. Kinase cascades are broadly employed for rapid transmission of extracellular information, thereby regulating the cell’s environmental response. These pathways play a prominent role in the inflammatory process. Several kinases directly phosphorylate histone proteins in chromatin, representing a mechanism for the rapid modification of chromatin with the potential to regulate selective transcription responses to environmental cues3-10. However, the molecular functions of specific histone phosphorylation events in transcription are poorly understood. Here, we demonstrate a direct effect of histone H3 phosphorylation at serine 28 (H3S28p) on transcription activation and describe a prominent role for H3S28p in the amplification of inflammatory gene transcription following stimulation of mouse macrophages with bacterial lipopolysaccharide (LPS). We identify MSK kinases as the non-redundant kinases that mediate the rapid, stimulation-dependent deposition of H3S28p on chromatin. Pharmacological approaches, including the use of a novel chemical agent, reveal that MSK inhibition abolishes stimulation-dependent accumulation of H3S28p at LPS-induced genes and reduces production of inflammatory gene products. Mechanistically, H3S28p directly increases transcriptional output by augmenting recruitment of the transcription co-activator and histone acetyltransferase (HAT) p300, and increasing its HAT activity. Our results reveal a delegated role for H3S28p in selective augmentation of transcription during the rapid cellular response to environmental cues.

ORGANISM(S): Mus musculus

PROVIDER: GSE63792 | GEO | 2016/10/31

SECONDARY ACCESSION(S): PRJNA269077

REPOSITORIES: GEO

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Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.

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Signaling to histone H3 for augmented transcription in the inflammatory response

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