B.S., University of Notre Dame
M.S., Indiana University - Purdue University Fort Wayne
Ph.D., University of Michigan
Postdoc, University of North Carolina at Chapel Hill
Garcia Lab – RNA Mechanisms and Neuromuscular Biology The overarching aim of my lab is to understand the fundamental roles that RNA play in both health and disease. Using Drosophila as a model system, the specific focus of my lab is the RNA mechanisms that contribute to neuromuscular diseases like SMA (Spinal Muscular Atrophy) and ALS (Amyotorophic Lateral Sclerosis). The lab uses new high throughput sequencing technologies and in-depth computational analysis together with classic molecular biology and fly genetics to unravel complex biological questions.
Cap control of RNA biogenesis in Drosophila melanogaster. The Cap Binding Complex (CBC) intertwines the processing of RNA 5'-ends with downstream steps in RNA biogenesis. The CBC consists of core Cap binding proteins (Cbp) and interchangeable Cbp-interacting proteins. The composition of the CBC largely determines the ultimate fate and biological function of the RNA. Arsenic resistance protein 2 (Ars2) in flies (Serrate/SRRT in plants and humans) is a Cbp-interacting protein that participates in the biogenesis of diverse types of RNA, including messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA). Ars2 also has non-CBC-associated protein-protein interactions that function in diverse RNA pathways, and it exhibits sequence-specific DNA-binding activity that functions in the self-renewal of stem cells. One of the projects in the lab utilizes high throughput sequencing approaches to unravel the multitude of RNA populations regulated by CBC-associated Ars2, which are likely distinct from other functions of Ars2 in RNA biogenesis.
RNA processing changes in Survival Motor Neuron (SMN) protein hypomorphs. When modeled in the fly, previous work has shown that SMA-causing point mutations found in patients recapitulate the full range of phenotypic severity seen in humans, genetic mutations in SMN that cause disease in humans also cause disease in flies. Transcriptomic comparison of SMN mutants with other snRNP biogenesis mutants revealed both distinct SMN mutant-specific and separate snRNP-dependent changes in gene expression and RNA processing. The relevance of these different sets of changes to disease pathology is not known. Another project in the lab employs transcriptomic analysis to assess the etiological significance of the identified RNA changes across different developmental stages and tissues, determining their relevance to SMA-like phenotypes.
Cellular proteostasis in fly models of SMA. Intriguingly, activation of innate-immune stress signaling is a common feature of both Drosophila and mammalian models of SMA. In flies, the activation of stress signaling from SMN loss mirrors the gene expression changes observed upon genetic disruption of the Integrated Stress Response (ISR). The ISR is a conserved pathway that links the endoplasmic reticulum and protein synthesis to diverse intrinsic and extrinsic signals. Using both genome-wide and gene-specific approaches, we are investigating the seeming overlap in snRNP biogenesis with the ISR pathway and the regulation of protein homeostasis (proteostasis). Our long-term goal is to understand the molecular interactions that intertwine ribonucleoprotein biogenesis with normal cellular homoeostasis and disease.
O’Hern, P.J., Garcia, E.L., Hao, L.T., Hart, A.L., Matera, A.G., Beattie, C.E. (2017) Chapter 14 – Non-mammalian animal models of Spinal Muscular Atrophy. In: Sumner CJ, Paushkin S, Ko C-P, eds., Spinal Muscular Atrophy: Disease Mechanisms and Therapy. San Diego: Academic Press: pp. 221-239
Garcia E.L., Wen Y., Praveen K., Matera A.G. (2016) Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant specific changes in pre-mRNA processing: implications for Spinal Muscular Atrophy. RNA 22:1215-1227 doi: 10.1261/rna.057208.116
Garcia E.L., Lu Z., Meers M.P., Praveen K., Matera A.G. (2013) Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes. RNA 19:1510-1516 doi: 10.1261/rna.038919.113