Neuroscience Graduate Program at UCSF
Identification and Characterization of Stochastic Choices in the Nervous System
Cells respond to the constantly changing environment by altering their gene expression profile. It is well documented in multiple systems that cues from the external world trigger signaling pathways that culminate in activation and repression of genes with great precision. Often though, the information that a cell receives from its environment is not sufficient to dictate the exact outcome of a gene expression program. In that situation cells need to make stochastic choices, having to select a fate among many available. In every scenario of stochastic decisions described in biology, the common theme is that a cell can select only one of the possible choices. For example, T and B cells express only one T or B cell receptor from the millions that they could possibly have, trypanosomes express only one out of few hundred vsg genes, malaria cells express only one out of 60 var genes and olfactory neurons express only one out of possible1300 olfactory receptor genes.
My scientific goal is understand the mechanism by which cells make stochastic choices and to identify more of these choices in the nervous system. We have shown that in the olfactory system, active olfactory receptor promoters interact with an enhancer element in trans. We believe that this interaction plays an important role in olfactory receptor expression. Using a high throughput approaches we found that an extensive network of interchromosomal interactions among potential enhancers coincides with olfactory receptor selection. Using multi-color DNA FISH we have shown that multiple enhancers located in different chromosomes co-localize in a specific locus in the nuclei of the olfactory neurons and that in this locus only an olfactory receptor gene can be transcribed. What are the molecules that bring these DNA elements together? What is the significance of keeping these elements in one locus? Why is only one olfactory receptor gene allowed to enter this locus? Using genetic and biochemical approaches we will attempt to answer these questions in my laboratory.
The discovery of a specific structure in the nucleus that is dedicated to the expression of olfactory receptors raises the question whether similar structures, dedicated to the expression of other genes exist in the central nervous system. We have developed a novel biochemical approach that detects interchromosomal interactions in an unbiased manner and we have applied it in numerous neuronal populations. We have identified this way numerous interactions that are detected in specific cell populations and we would like to understand the role that they play in regulation of gene expression and the generation of the extreme diversity observed in the nervous system.
Finally my lab is focusing in the role of epigenetic changes in behavior. We are investigating the role that DNA methylation and histone modifications might be playing in the construction of the brain and the generation of certain behavioral responses in mice.
Magklara A, Yen A, Colquitt BM, Clowney EJ, Allen W, Markenscoff-Papadimitriou E, Evans ZA, Kheradpour P, Mountoufaris G, Carey C, Barnea G, Kellis M, Lomvardas S. (2011). An epigenetic signature for monoallelic olfactory receptor expression. Cell 145:555-570. PMCID: PMC3094500
Clowney EJ, Magklara A, Colquitt BM, Pathak N, Lane RP, Lomvardas S. (2011).High-throughput mapping of the promoters of the mouse olfactory receptor genes reveals a new type of mammalian promoter and provides insight into olfactory receptor gene regulation. Genome Research 21, 1249-1259. PMCID: PMC3149492
Birnbaum R., Clowney E.J., Agamy, O., Kim M.J., Zhao J., Yamanaka T., Pappalardo Z., Clarke S.L., Wenger A.M., Nguyen L., Gurrieri F., Everman D., Schwartz C.E., Birk O.S., Bejerano G., Lomvardas S., Ahituv N. (2012). Coding exons function as tissue-specific enhancers of nearby genes. Genome Research (22) 6 1059-1068. PMCID: PMC3371700
Johnson M.A., Tsai L., Roy D.S., Valenzuela D.H., Mosley C., Magklara A., Lomvardas S., Liberles S.D. and Barnea G. (2012) Neurons expressing trace amine-associated receptors project to discrete glomeruli and constitute an olfactory subsystem. PNAS 109 (33) 13410-13415. PMC3421222
Clowney E.J., LeGross M.A., Mosley C.M., Clowney F.G., Markenskoff-Papadimitriou E.C., Myllys M., Barnea G., Larabell C.A. and Lomvardas, S. (2012) Nuclear aggregation of olfactory receptor genes regulates their monogenic expression. Cell 151:724-737. PMID: 23141535
Kevin Monahan and Stavros Lomvardas (2012). How keeping active pays off in the olfactory system eLife1:e00070. PMCID: PMC3510477
Angeliki Magklara and Stavros Lomvardas (2013). Mechanisms of stochastic gene expression: lessons from olfaction (ePub ahead of print May 18 2013) Trends in Cell Biology
Lyons B.D., Allen W.E., Goh, T., Tsai, L., Barnea G. and Lomvardas S. (2013). An epigenetic trap stabilizes singular olfactory receptor expression. Cell 154(2): 325-336
Colquitt B.M., Allen W.E., Barnea G. and Lomvardas S. (2013). Alteration of genic 5-hydroxymethylcytosine levels in olfactory neurons correlates with changes in gene expression and cell identity. PNAS (in press).
Agalioti, T., Lomvardas, S., Parekh, B., Yie, J., Maniatis, T., and Thanos, D. (2000). Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 103:667-678.
Munshi, N., Agalioti, T., Lomvardas, S., Merika, M., Chen, G. and Thanos D. Coordination of a transcriptional switch by HMGI(Y) acetylation. (2001). Science 293: 1133-1136.
Lomvardas, S. and Thanos, D. (2001). Nucleosome sliding via TBP DNA binding in vivo. Cell 106: 685-696.
Lomvardas, S. and Thanos, D. (2002). Opening Chromatin. Mol. Cell 2: 209-211.
Lomvardas, S. and Thanos, D. (2002). Modifying gene expression programs by altering core promoter chromatin architecture. Cell 110: 261-271.
Guan, Z., Giustetto, M., Lomvardas, S., Kim, J.H., Miniaci, M.C., Schwartz, J.H., Thanos, D. and and Kandel, E.R. (2002). Integration of long-term memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111: 483-493.
Lomvardas, S., Barnea, G., Pisapia, J.D., and Axel, R. (2006). Interchromosomal interactions and olfactory receptor choice. Cell, 126: 403-413.
Stavros Lomvardas, Ph.D.
UCSF MC 2822
1550 4th Street, RH-348D
San Francisco, CA 94158
Mission Bay Campus