Exposure to environmental toxins threatens the integrity of the genome by causing mutations that can perturb the carefully regulated expression of genes. When toxins damage DNA, the cell launches a response to pause potentially affected processes and attempt repair. Thus, the DNA damage response (DDR) involves a shift in gene expression state;these shifts are typically orchestrated by epigenetic changes to the genome. Indeed, modifications to chromatin are required to launch the DDR gene expression program. In many diverse cellular processes, long noncoding RNAs (lncRNAs) have been recently shown to play an important role in chromatin modification by binding and localizing chromatin-modifying proteins. IncRNAs are a huge new class of genes whose functional mechanisms are an area of active research. Here, the investigators will perform integrative analysis of diverse genome-wide experimental datasets to place lncRNAs into chromatin modification pathways in the DDR and describe their functional mechanisms via RNA motifs. Specifically, the investigators'research has the following aims: 1) Discover lncRNAs important to the DDR via RNA sequencing throughout a time course after environmental toxin exposure. 2) Annotate DDR dynamics of genome-wide chromatins states and lncRNA-protein interactions using quantitative sequencing assays throughout a time course after environmental toxin exposure. 3) Integrate lncRNA-chromatin data to describe lncRNA motifs and chromatin modification mechanisms in the DDR. Successful completion of these aims will produce a more detailed understanding of the entities and mechanisms executing the chromatin modification processes in the DDR. The computational methods developed will be widely applicable for future integrative computational biology analyses in any cellular context.

Public Health Relevance

The research objective of this application is to integrate long noncoding RNAs (lncRNAs) into cellular pathways involved in the DNA damage response (DDR) to environmental toxins and map the RNA motif interactions with proteins that are crucial to the concomitant chromatin modifications. The DDR is critical to maintain the integrity of the genome against mutations that can cause disease, particularly cancer. Studying the relationship between lncRNAs and the chromatin modifications of the DDR will give a better understanding of how mutations in noncoding sequence can incapacitate the DDR and cause disease.

National Institute of Health (NIH)
Mentored Quantitative Research Career Development Award (K25)
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Special Emphasis Panel (ZES1)
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Tyson, Frederick L
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Harvard University
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Kelley, David R; Snoek, Jasper; Rinn, John L (2016) Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks. Genome Res 26:990-9
G Hendrickson, David; Kelley, David R; Tenen, Danielle et al. (2016) Widespread RNA binding by chromatin-associated proteins. Genome Biol 17:28
Kelley, David R; Hendrickson, David G; Tenen, Danielle et al. (2014) Transposable elements modulate human RNA abundance and splicing via specific RNA-protein interactions. Genome Biol 15:537