Telomerase promoter reprogramming and interaction with general transcription factors in the human mesenchymal stem cell.
The human adult mesenchymal stem cell (hMSC) does not express telomerase and has been shown to be the target for neoplastic transformation after transduction with hTERT. These findings lend support to the stem cell hypothesis of cancer development but by supplying hTERT, the molecular events required to upregulate hTERT expression in cancer development are missed. Therefore, the hMSC is ideal for the identification of molecular mechanisms regulating telomerase gene expression in stem cells. This study shows that the repression of hTERT expression in hMSC is chromatin based and that modifications of the chromatin environment lead to reactivation of telomerase gene expression. It is shown that repression of hTERT expression in hMSCs is due to promoter-specific histone hypoacetylation coupled with low Pol II and TFIIB trafficking. This repression is overcome by treatment with Trichostatin A (TSA), an HDAC inhibitor, concomitant with increases in promoter-specific histone acetylation and increases in Pol II and TFIIB tracking. hTR expression is also increased in TSA-treated hMSCs, concomitant with changes in Pol II and TFIIB dynamics.
Serakinci
Nedime
N
University of Southern Denmark, Institute of Medical Biology, Department of Anatomy and Neurobiology, Odense C, Denmark.
Hoare
Stacey F
SF
Kassem
Moustapha
M
Atkinson
Stuart P
SP
Keith
W Nicol
WN
D000107:Acetylation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004257:DNA Polymerase II / Q000378:metabolism; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D012313:RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D035581:Transcription Factor TFIIB / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D035581:Transcription Factor TFIIB; D014157:Transcription Factors; C422952:telomerase RNA; D012313:RNA; D051548:Histone Acetyltransferases; C509186:TERT protein, human; D019098:Telomerase; D004257:DNA Polymerase II