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Ki Youb Park

Mentor: Andrew Russo, Ph.D.
Lab Phone: 335-7873

Transcriptional regulation of neuropeptide calcitonin gene-related peptide (CGRP)

The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. CGRP levels are elevated in migraine and since migraine lasts up to 72 hours, CGRP gene expression in trigeminal ganglia is speculated to also be elevated. The transcription factors, upstream stimulatory factor (USF) 1 and 2, bind the cell-specific 18-bp enhancer of the CGRP gene. Interestingly, even though USF proteins are ubiquitous, CGRP is exclusively expressed in neurons. To elucidate how ubiquitous USF can specifically activate CGRP gene in neurons, I took two approaches. First, I performed immunohistochemistry to observe USF proteins in trigeminal ganglia tissue. USF1 immunoreactive signal was greater in neurons than in non-neuronal cells, while USF2 staining was similar in neurons and non-neuronal cells. USF1 was predominantly localized in nuclei, while localization of USF2 was more diverse. Upon treatment with sorbitol, more USF2 signal was detected in the nuclei. This suggests that USF1 is responsible for basal neuronal specific CGRP gene expression and USF2 for stimulated CGRP gene expression. Secondly, I examined histone acetylation at the 18-bp enhancer by performing chromatin immunoprecipitation assay. I found that histone H3 was more acetylated at the 18-bp enhancer in CGRP-expressing cell line (CA77) than in CGRP-not-expressing cell line (Rat2). Treatment of trichostatin A increased CGRP mRNA level in CA77, but not in Rat2 cells. These data support that chromatin might be in an open state at the 18-bp enhancer, leading to the cell-specific CGRP transcription. These studies on the mechanisms of CGRP gene regulation may possibly help our understanding of the pathophysiology of migraine at the molecular level.

Park KY, Fletcher JR, Raddant AC, Russo AF. Epigenetic regulation of the calcitonin gene-related peptide gene in trigeminal glia. Cephalalgia. 2011 Apr;31(5):614-24. Epub 2011 Jan 7. PubMed PMID: 21216873; PubMed Central PMCID:PMC3383834.

Park KY, Russo AF. Control of the calcitonin gene-related peptide enhancer by upstream stimulatory factor in trigeminal ganglion neurons. J Biol Chem. 2008 Feb 29;283(9):5441-51. Epub 2007 Dec 31. PubMed PMID: 18167349.