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


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.
Wang
Bo
B
Centre for Vascular Research, University of New South Wales, Sydney NSW 2052, Australia.
Chen
Jinbiao
J
Santiago
Fernando S
FS
Janes
Mary
M
Kavurma
Mary M
MM
Chong
Beng H
BH
Pimanda
John E
JE
Khachigian
Levon M
LM
D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D006657:Histones; D053583:Interleukin-1beta; D048049:Extracellular Signal-Regulated MAP Kinases