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Epigenetic mechanisms of hTERT regulation in aging human cells.

The enzyme telomerase is a critical component in the processes that control chromosomal stability, cellular senescence, and neoplastic transformation. While absent in most somatic cell lines, expression of telomeraseis catalytic subunit, hTERT, occurs in the highly proliferative tissues of the endometrium, hematopoietic cells, and greater than 90% of cancers. As hTERT mRNA levels correspond directly to enzymatic activity, regulatory mechanisms governing the transcription of this gene have thus been identified as important targets for a variety of potential therapies seeking to inhibit telomerase. The sodium bisulfite sequencing method, which distinguishes between methylated and unmethylated cytosine residues, will be used to assess 5-methylcytosine levels in WI-38 fetal lung fibroblasts, a well-characterized system for studying aging and telomerase. Despite the knowledge that upstream factors important in hTERT transcription are subject to methylation control and that others are known to interact with chromatin remodeling enzymes, the effects of epigenetics on telomerase expression remain controversial. While some researchers have shown an association between hTERT promoter hypermethylation and gene expression in cancer cell lines, exceptional cases of expression and associated hTERT hypomethylation have been reported in a lymphocytic leukemia and in a human teratocarcinoma cell line. This study proposes to analyze the effects of site-specific DNA methylation in the hTERT promoter region in aging cells. Understanding of the role of epigenetic processes in telomerase regulation during cellular senescence will provide critical information about the natural processes that lead to loss of expression stability with aging in this gene.

Nathaniel J. Hansen, Liang Liu, Rebecca C. Wylie, Payal Patel, Brian M. Bowman, Mitchell S. Pate, Lucy G. Andrews and Trygve O. Tollefsbol. Dept. of Biology, Univ. of Alabama at Birmingham, Birmingham, AL 35294.
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Title Annotation:Biological Sciences
Author:Hansen, Nathaniel J.; Liu, Liang; Wylie, Rebecca C.; Patel, Payal; Bowman, Brian M.; Pate, Mitchell
Publication:Journal of the Alabama Academy of Science
Article Type:Brief Article
Date:Apr 1, 2003
Words:277
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