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Phosphorylation and acetylation of histone H3 and autoregulation by early growth response 1 mediate interleukin 1beta induction of early growth response 1 transcription.

Wang B., Chen J., Santiago F.S., Janes M., Kavurma M.M., Chong B.H., Pimanda J.E., Khachigian L.M.

OBJECTIVE: The transcription factor early growth response (EGR)-1 has been implicated as a key vascular phenotypic switch through its control of inducible transcription. EGR-1 autoregulation, and histone modification in the EGR-1 promoter, represent key mechanisms in EGR-1 control, but have not been explored. METHODS AND RESULTS: We demonstrate that EGR-1 regulates its own transcription and that this involves histone H3 phosphorylation and acetylation. EGR-1 transactivates its promoter in smooth muscle cells exposed to interleukin (IL) 1beta through a novel cis-acting element (-211/-203). PD98059, which inhibits mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) attenuates IL-1beta-inducible phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen and stress-activated protein kinases 1/2; and reduces levels of phosphorylated and acetylated histone H3. Histone deacetylase inhibition enhances EGR-1 transcription in response to cytokine. Conversely, suppression of histone modification with mitogen and stress-activated protein kinase 1/2 short interfering RNA, or the histone H3 acetyltransferase inhibitor Garcinol, inhibits IL-1beta-inducible EGR-1 transcription. EGR-1 interacts with the acetyltransferase p300. Acetylated H3 and phosphorylated H3 are enriched at the promoter of EGR-1; and EGR-1 is enriched at the promoters of tissue factor and plasminogen activator inhibitor 1 in response to IL-1beta, and attenuated by PD98059, Garcinol, and mitogen and stress-activated protein kinase 1/2 short interfering RNA. CONCLUSIONS: IL-1beta induction of EGR-1 transcription involves histone H3 phosphorylation, acetylation, and autoregulation by EGR-1.

Arterioscler. Thromb. Vasc. Biol. 30:536-545(2010) [PubMed] [Europe PMC]

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