This proposal, Regulatory role of long noncoding RNAs in normal and cancer cells?, is being submitted in response to PAR-17-049, Research Specialist (laboratory-based Scientists) Award (R50), from the National Cancer Institute. The Award is designed to encourage the development of stable research career opportunities for exceptional scientists who want to pursue research within the context of an existing cancer research program, but not serve as independent investigators. This proposal is built on the Outstanding Investigator Award (R35) received by Dr. Daniel G. Tenen in response to PAR-14-267 and entitled Mechanisms of regulation by RNA in acute myeloid leukemia?. In recent years researchers have revealed that a large portion of the genome of complex organisms are transcribed but not translated. These noncoding RNAs (ncRNAs) provide an additional and relatively unexplored layer of control to many biological processes. The overall goal of the R35 proposal is to investigate underexplored aspects of RNA control in cancer, using acute myeloid leukemia (AML) as a model of study. The contribution of the Research Scientist will aim at understanding, in the context of a cancer environment, the mechanistic role played by RNAs, by addressing the following areas: (1) the study of a noncoding RNA which limits expression of the tumor suppressor gene PU.1, particularly in a specific subsets of leukemias; and (2) the ability of ncRNA to regulate epigenetic changes such as DNA methylation, with the ultimate goal of developing gene-selective demethylating tools as well as identifying other epigenetic marks regulated by ncRNAs. These studies will, in every instance, seek to investigate the role of ncRNAs in cancer, as well as potential development of more specific therapeutic modalities. In addition, to the goals listed in the Dr. Tenen?s R35 proposal, I propose to extend the studies within the following research areas: (i) Understanding the role of lncRNAs in maintaining stability of genomic DNA; (ii) Understanding the role of lncRNAs in formation of transcriptionally active chromatin; and (iii) Identification of lncRNAs involved in maintaining stability of the genomic DNA in acute myeloid leukemia. Fulfilment of these new directions will be a logical continuation of the ideas proposed in Dr. Tenen?s application and might pave the way for the future translational efforts.
Recent years have seen an explosion in the study of the noncoding part of our genome, which includes more than 90% of our DNA, and the RNAs emanating from these regions. In this proposal, we will investigate three very novel and understudied aspects of RNA biology, including antisense RNAs, which are in a direction opposite of most genes, and the role of RNA in methylation. We will develop tools and methods to alter these processes, which if successful have the potential to have great impact in diseases including leukemia and other cancers.