Phosphorylation and Acetylation of Histone H3 and Autoregulation by Early Growth Response 1 Mediate Interleukin 1β Induction of Early Growth Response 1 Transcription

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) 1β through a novel cis -acting element (−211/−203). PD98059, which inhibits mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) attenuates IL-1β–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-1β–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-1β, and attenuated by PD98059, Garcinol, and mitogen and stress–activated protein kinase 1/2 short interfering RNA. Conclusion— IL-1β induction of EGR-1 transcription involves histone H3 phosphorylation, acetylation, and autoregulation by EGR-1.