H-105 Reinhard Kurth Memorial Lecture: the Non-coding Transcriptome

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Abstract

We have identified a small molecule inhibitor of MYC. The compound inhibits the MYC transcriptional program and is effective in blocking the growth of MYC-driven xenotransplants. The characterization of this inhibitor led to the discovery that MYC regulates a large proportion of the non-coding transcriptome. Cellular levels of MYC affect virtually all non-coding transcripts either positively or negatively. MYC binds to promoter-proximal sites of non-coding transcripts and therefore appears to act directly, not through the agency of a subordinate transcriptional regulator. This effect of MYC on the non-coding transcriptome has been confirmed by RNAseq, qRT-PCR and nuclear run-on and is in accord with global epigenetic and ChIP data. An important and still poorly understood feature of this regulatory action of MYC is that MYC binding to transcriptional start sites is identical across different cell lines, but the resulting expression patterns are cell line-specific. The factors involved in this specificity have not been identified. The regulation of the non-coding transcriptome by MYC constitutes a huge expansion of MYC activity and amounts to multiplying the MYC universe. Because of the oncogenic potential of MYC, we investigated non-coding transcriptomes for cancer-specific lncRNAs. We identified several such lncRNAs, including one that is specific for luminal breast cancer, is exported from the cancer cells by an exosomal mechanism and is taken up by surrounding, non-expressing cells. Functional characterizations of lncRNAs that are specific for a certain cancer type are in progress.

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