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Institute for Genetic Medicine
733 N. Broadway
Baltimore MD 21205
Long non-coding RNAs in neural cell fate decisions
The goal of my research program is to answer a fundamental biological question: how is the genome properly interpreted to coordinate the diversity of cell types observed during neuronal development? We are focused on the acquisition of specific cellular identities in neuronal development and identifying the molecular determinants responsible for proper brain development. Using novel experimental approaches for the enrichment and purification of specific neuronal cell types, and recent technological advances in single-cell RNA sequencing, we can discover and explore the cellular factors that contribute to neuronal cell fate decisions during mammalian brain development. We use these approaches to establish high-resolution time courses of neuronal differentiation and maturation. Much of our work is focused on the 'noncoding genome' and in particular, a specific class of molecules known as long noncoding RNAs (lncRNAs). LncRNAs represent a recently-formalized class of RNA molecules with established roles in differentiation, cell fate specification, apoptosis, and various disorders. The flexibility of RNA as a functional substrate, the observed tissue and cell type specificity of these molecules, and their abundance and exquisite spatio-temporal regulation in the developing brain suggest that these genes are uniquely poised to contribute to the observed heterogeneity of the mammalian brain. My group is interested in the mechanisms by which lncRNAs regulate target gene expression in the context of neuronal differentiation, their coordinate interactions with regulatory protein complexes, their association with neurodevelopmental disorders, and their functional roles in establishment and maintenance of specific neuronal phenotypes.
Goff LA, Groff AF, Sauvageau M, Trayes-Gibson Z, Sanchez-Gomez DB, Morse M, Martin RD, Elcavage LE, Liapis SC, Gonzalez-Celeiro M, Plana O, Li E, Gerhardinger C, Tomassy GS, Arlotta P, Rinn JL. 2015. Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain. PNAS Jun 2;112(22):6855-62.
Molyneaux BJ*, Goff LA*, Brettler AC, Chen HH, Brown JR, Hrvatin S, Rinn JL, Arlotta P. 2014 DeCoN: genome-wide analysis of in vivo transcriptional dynamics during pyramidal neuron fate selection in neocortex. Neuron. Jan 21;85(2):275-88.
Sauvageau, M.*, Goff, L.A.*, Lodato, S.*, Bonev, B., Groff, A.F., Gerhardinger, C., Sanchez-Gomez, D., Hacisuleyman, E., Li, E., Spence, M., Liapis, S., Mallard, W., Morse, M., Swerdel, M., D’Ecclessis, M., Moore, J., Lai, V., Gong, G., Yancopolous, G., Frendewey, D., Kellis, M., Hart, R.P., Valenzuela, D., Arlotta, P., Rinn, J.L., (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. eLife 2013; 2:e01749 *Authors contributed equally
Hacisuleyman, E.*, Goff, L.A.*, Trapnell, C., Sauvageau, M., Hendrickson, D., Kelley, D.R., McClanahan, P., Williams, A., Henao-Mejia, J., Sun, L., Engreitz, J., Guttman, M., Lander, E.S., Flavell, R., Lodish, H.F., Raj, A., Rinn, J.L. (2014) Topological organization of multi-chromosomal regions by the long intergenic noncoding RNA Firre. Nature Structural & Molecular Biology. 2014 Jan 26 *Authors contributed equally.
Lodato, S., Molyneaux, B.J., Zuccaro, E., Goff, L.A., Chen, H., Yuan, W., Meleski, A., Takahashi, E., Mahoney, S., Rinn, J.L., Gifford, D.K., Arlotta, P. (2014) Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nature Neuroscience. 17:1046-1054.
Davila, J.L.*, Goff, L.A.*, Ricupero, C.L.*, Camarilla, C., Oni, E.N., Swerdel, M.R., Toro-Ramos, A.J., Li, J., Hart, R.P. (2014) A positive feedback mechanism that regulates expression of miR-9 during neurogenesis. PLoS One. April 2014 9(4):e94348. *Authors contributed equally.
Di Ruscio, A., Ebralidze, A.K., Benoukraf, T., Amabile, G., Goff, L.A., Alberich-Jorda, M., Pradhan, S., Figueroa, M.E., D’Alo, F., Wu, M., Leone, G., Rinn, J.L., Tenen, D.G., (2013) DNMT1-non-coding RNA interaction modulates locus specific DNA methylation. Nature, 503:371-376.
Henao-Mejia, J., Williams, A., Goff, L.A., Staron, M., Licona-Limon, P., Kaech, S.M., Nakayama, M., Rinn, J.L., Flavell, R.A., (2013) The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell. ontogenesis and lymphocyte development and homeostasis. Immunity, 38(5):984-97.
Trapnell, C., Hendrickson, D.G., Sauvageau, M., Goff, L.A., Rinn, J.L., Pachter, L., (2013) Differential analysis of gene at transcript resolution with RNA-Seq. Nature Biotechnology 31:46-53. PubMed Reference Sun, L.*, Goff, L.A.*, Trapnell, C.*, Alexander, R., Lo, K.A., Kellis, M., Lodish, H., Rinn, J.L., (2013) Long noncoding RNAs regulate adipogenesis, PNAS 11(9):3387-3392 *Authors contributed equally
Trapnell, C., Roberts, A., Goff, L.A., Pertea, G., Kim, D., Kelley, D. Pimentel, H., Salzberg, S., Rinn, J.L., Pachter, L., (2012) Differential Gene and Transcript Expression Analysis of RNA-Seq Experiments with TopHat and Cufflinks. Nature Protocols 7(3):562-578.
Pichardo-Casas, I., Goff, L.A., Swerdel, M.R., Athie, A., Davila, J., Ramos-Brossier, M., Lapid-Volosin, M., Friedman, W., Hart, R.P., Vaca, L., (2012) Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced regulation, Brain Research. 1436:20-33.
Cabili, N.M., Trapnell, C.B., Goff, L.A., Koziol, M.,Tazon-Vega, B., Regev, A., Rinn, J.L., (2011) Integrative analysis of human large intergenic non-coding RNAs reveals global properties and specific subclasses, Genes & Development, Advance online publication, 25:000-000 doi:10.1101/gad.17446611.
Goff, L.A., Davila, J., Swerdel, M.R., Moore, J.C., Cohen, R.I., Wu, H., Sun, Y.E., Hart, R.P., (2009) Ago2 immunoprecipitation identifies predicted microRNAs in human embryonic stem cells and neural precursors, PLoS One (4)9: e7192, doi:10.1371/journal.pone.0007192.
Chang, Y., Goff, L.A., Li, H., Kane-Goldsmith, N., Tzatzalos, E., Hart, R.P., Young, W., Grumet, M., (2009) Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation, Journal of Neurotrauma. 26(7): 979-993
Li, H., Han, Y., Bi, C., Davila, J.,Goff, L.A., Thompson, K., Swerdel, M., Camarillo, C., Ricupero, C.L., Hart, R.P., Plummer, M.R., Grumet, M., (2008) Functional differentiation of a clone resembling embryonic cortical interneuron progenitors, Developmental Neurobiology. 68(14): 1549-64. PubMed Reference Goff, L.A., Boucher, S., Ricupero, C.L., Fenstermacher, S., Swerdel, M., Chase, L.G., Adams, C.C., Chesnut, J., Lakshmipathy, U., Hart, R.P., (2008) Differentiating human multipotent mesenchymal stromal cells regulate microRNAs: prediction of microRNAs regulation by PDGF during osteogenesis, J. Exp. Hematology. 36(10): 1354-1369