Many biological processes, from early development to the immune response, rely on the “non-coding†part of the genome, about which researchers have much to learn. An organism’s DNA can be separated into two categories: coding DNA, which has the directions for how to build proteins – the molecular machines of the cell, and non-coding DNA, which has many functions including the instructions for when, where, and how much protein should be built. The majority of the human genome is non-coding DNA, and its proper functioning is essential for life. This project aims to decipher some of the rules that govern function of non-coding DNA in the innate immune response to infection and to compare these rules to non-coding DNA needed for other biological processes. Success will give scientists specific information about how non-coding DNA orchestrates the immune response and a deeper understanding about how a large part of the genome functions in general. Both graduate and undergraduate students will participate and be trained in the work. This project also includes a broader impacts plan to improve quantitative literacy among biology undergraduate and graduate students, which will better equip them for modern jobs that increasingly require quantitative skills.
Virtually every biological process, from development to immunity, is controlled by a gene regulatory network (GRN), a network of signaling molecules and transcription factors that control gene expression. Years of work have uncovered how the sequence of regulatory DNA, e.g. promoters and enhancers, can specify a GRN’s function. This work largely has focused on developmental GRNs, which are uniquely constrained by evolution: selection favors GRNs that drive a stereotyped developmental program in spite of perturbations. To decipher which principles of developmental GRNs translate to lesser studied non-developmental GRNs, which have diverse functions and are subject to different evolutionary pressures, this project will study the Drosophila innate immunity GRN. In Aim 1, allele-specific RNA-seq will be used to characterize the natural variation in transcriptional response to infection between D. melanogaster lines. These data will allow the identification of genes whose expression variation is driven by changes in regulatory DNA. Comparisons of the pattern of expression variation using different infection conditions will be made. In Aim 2, in vivo and in vitro functional genomics assays will be used to identify immune-responsive enhancers and to generate sequence-to-function models of these enhancers. Additional experiments will validate and refine the models of enhancer function. The project also includes a plan to implement problem-based learning of numerical literacy components into a large, undergraduate class, which will improve the quantitive skills of biology students and be disseminated for use by others.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
