Genomics

Dataset Information

25

GABP determines the epigenetic status of mutant TERT promoter


ABSTRACT: Blocking telomerase is recognized as a key anti-cancer mechanism. Unlike in stem cells, levels of telomerase catalytic subunit TERT are limiting in reconstituting telomerase activity in somatic cells. However in some cancers, Tert is transcriptionally reactivated by mutations in its promoter. Given that Tert in stem cells is driven by WT Tert promoter, if we can selectively target Tert reactivation through mutant Tert promoters we can block telomerase activity specifically in cancer cells without toxicity in stem cells. Here we report the epigenetic regulation of Tert promoter comparing WT and mutant promoters. We showed that GABPA homodimerization through long-range interaction stabilizes Gabpa to drive Tert expression. Furthermore, BRD4 specifically activates the C250T mutant promoter via dual mechanism involving GABPA, thereby setting the stage for future therapeutics. Overall design: We examine 2 biological replicates of each sample including BLM, A375, BLM6 (Crispr-Tert mutant promoter C250T) and BLM14 (Crispr-Tert WT promoter C250C )

INSTRUMENT(S): Illumina MiSeq (Homo sapiens)

SUBMITTER: Melissa Jane Fullwood 

PROVIDER: GSE77265 | GEO | 2017-02-27

SECONDARY ACCESSION(S): PRJNA309931

REPOSITORIES: GEO

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Publications

Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation.

Akıncılar Semih Can SC   Khattar Ekta E   Boon Priscilla Li Shan PL   Unal Bilal B   Fullwood Melissa Jane MJ   Tergaonkar Vinay V  

Cancer discovery 20160920 11


Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction  ...[more]

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