Recently, we discovered a new mechanism for cancer pathogenesis that does not require mutations in the DNA sequence. We found widespread expression of mRNAs with shorter 3'untranslated regions (3'UTRs) in cancer cells which was due to recognition of alternative cleavage and polyadenylation signals (ApA). The shortening of 3'UTRs of oncogenes led to increased protein levels which was sufficient for oncogenic transformation. However, shortening of 3'UTRs was also seen during physiological processes such as activation of T cells. In the long term, we want to find the mechanism for the generation of mRNAs with different 3'UTRs and determine the overall functional consequences of differential expression of 3'UTR isoforms for cancer. We will start by defining all mRNA 3'ends of the transcriptome in isogenic pairs of normal and transformed cells as well as in early and late stages of tumor development to identify the cancer-specific changes in 3'UTR expression. To do so, we will apply next-generation sequencing technology using our own protocol (3'-seq) to map mRNA 3'ends quantitatively. To start to address the functional consequences of mRNAs with shorter and longer 3'UTRs, we will use 3'-seq to determine the mRNA stability rates for all alternative mRNA isoforms to discover new (in)stability elements in 3'UTRs. To begin to identify causal factors for the shift in ApA signal choice, we will examine chromatin architecture at the 3'ends of transcription units since RNA processing occurs co-transcriptionally and in close proximity to RNA polymerase II and chromatin. We have preliminary data that histone variants and chromatin-associated factors influence ApA signal choice. Chromatin immunoprecipitation data and 3'-seq data will be correlated to describe the marks that are associated with the canonical 3'end of a gene and whose presence is altered upon expression of alternative 3'ends of mRNAs in activated and cancer states. This study will elucidate an important new mechanism of cancer pathogenesis. Better understanding of this mechanism may lay the groundwork for reversing this cancer-related pathway by therapeutic intervention.

Public Health Relevance

We found a new mechanism for cancer formation that involves expression of shorter mRNAs in cancer cells. This mechanism is also used in normal cellular processes. We will investigate the causes and consequences of this mechanism for normal and cancer cells to identify the cancer-specific changes. This will further our understanding of cancer biology and might lay the groundwork for new therapeutic options in cancer.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1)
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Li, Jerry
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New York
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Lianoglou, Steve; Garg, Vidur; Yang, Julie L et al. (2013) Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev 27:2380-96