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Articles by M. J Hitchler
Total Records ( 1 ) for M. J Hitchler
  G. W Woodfield , M. J Hitchler , Y Chen , F. E Domann and R. J. Weigel

Purpose: Transcriptional regulation of estrogen receptor- (ER) involves both epigenetic mechanisms and trans-active factors, such as TFAP2C, which induces ER transcription through an AP-2 regulatory region in the ER promoter. Attempts to induce endogenous ER expression in ER-negative breast carcinomas by forced overexpression of TFAP2C have not been successful. We hypothesize that epigenetic chromatin structure alters the activity of TFAP2C at the ER promoter.

Experimental Design: DNA methylation, histone acetylation, and chromatin accessibility were examined at the ER promoter in a panel of breast carcinoma cell lines. TFAP2C and polymerase II binding were analyzed by chromatin immunoprecipitation. Epigenetic chromatin structure was altered using drug treatment with 5-aza-2'-deoxycytidine (AZA) and trichostatin A (TSA).

Results: The ER promoter in the ER-negative lines MDA-MB-231, MCF10A, and MCF7-5C show CpG island methylation, histone 3 lysine 9 deacetylation, and decreased chromatin accessibility compared with ER-positive cell lines MCF7 and T47-D. Treatment with AZA/TSA increased chromatin accessibility at the ER promoter and allowed TFAP2C to induce ER expression in ER-negative cells. Chromatin immunoprecipitation analysis showed that binding of TFAP2C to the ER promoter is blocked in ER-negative cells but that treatment with AZA/TSA enabled TFAP2C and polymerase II binding.

Conclusion: We conclude that the activity of TFAP2C at specific target genes depends upon epigenetic chromatin structure. Furthermore, the combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ER gene in ER-negative breast cancer cells.

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