Browsing by Author "Skene, JH Pate"

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    Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.
    (J Clin Invest, 2010-05) Iskandar, Bermans J; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H; Jarrard, David F; Banerjee, Ruma V; Skene, JH Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D; Hogan, Kirk J
    The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.
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    Genetic origins of social networks in rhesus macaques.
    (Scientific reports, 2013-01-09) Brent, Lauren JN; Heilbronner, Sarah R; Horvath, Julie E; Gonzalez-Martinez, Janis; Ruiz-Lambides, Angelina; Robinson, Athy G; Skene, JH Pate; Platt, Michael L
    Sociality is believed to have evolved as a strategy for animals to cope with their environments. Yet the genetic basis of sociality remains unclear. Here we provide evidence that social network tendencies are heritable in a gregarious primate. The tendency for rhesus macaques, Macaca mulatta, to be tied affiliatively to others via connections mediated by their social partners - analogous to friends of friends in people - demonstrated additive genetic variance. Affiliative tendencies were predicted by genetic variation at two loci involved in serotonergic signalling, although this result did not withstand correction for multiple tests. Aggressive tendencies were also heritable and were related to reproductive output, a fitness proxy. Our findings suggest that, like humans, the skills and temperaments that shape the formation of multi-agent relationships have a genetic basis in nonhuman primates, and, as such, begin to fill the gaps in our understanding of the genetic basis of sociality.
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    Long-Chain Fatty Acylation of Proteins
    Patterson, Sean I; Skene, JH Pate
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    Nociceptor-Enriched Genes Required for Normal Thermal Nociception.
    (Cell reports, 2016-07) Honjo, Ken; Mauthner, Stephanie E; Wang, Yu; Skene, JH Pate; Tracey, W Daniel
    Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals.
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    OntologyWidget - a reusable, embeddable widget for easily locating ontology terms.
    (BMC bioinformatics, 2007-09-13) Beauheim, Catherine C; Wymore, Farrell; Nitzberg, Michael; Zachariah, Zachariah K; Jin, Heng; Skene, JH Pate; Ball, Catherine A; Sherlock, Gavin
    Biomedical ontologies are being widely used to annotate biological data in a computer-accessible, consistent and well-defined manner. However, due to their size and complexity, annotating data with appropriate terms from an ontology is often challenging for experts and non-experts alike, because there exist few tools that allow one to quickly find relevant ontology terms to easily populate a web form.We have produced a tool, OntologyWidget, which allows users to rapidly search for and browse ontology terms. OntologyWidget can easily be embedded in other web-based applications. OntologyWidget is written using AJAX (Asynchronous JavaScript and XML) and has two related elements. The first is a dynamic auto-complete ontology search feature. As a user enters characters into the search box, the appropriate ontology is queried remotely for terms that match the typed-in text, and the query results populate a drop-down list with all potential matches. Upon selection of a term from the list, the user can locate this term within a generic and dynamic ontology browser, which comprises the second element of the tool. The ontology browser shows the paths from a selected term to the root as well as parent/child tree hierarchies. We have implemented web services at the Stanford Microarray Database (SMD), which provide the OntologyWidget with access to over 40 ontologies from the Open Biological Ontology (OBO) website 1. Each ontology is updated weekly. Adopters of the OntologyWidget can either use SMD's web services, or elect to rely on their own. Deploying the OntologyWidget can be accomplished in three simple steps: (1) install Apache Tomcat 2 on one's web server, (2) download and install the OntologyWidget servlet stub that provides access to the SMD ontology web services, and (3) create an html (HyperText Markup Language) file that refers to the OntologyWidget using a simple, well-defined format.We have developed OntologyWidget, an easy-to-use ontology search and display tool that can be used on any web page by creating a simple html description. OntologyWidget provides a rapid auto-complete search function paired with an interactive tree display. We have developed a web service layer that communicates between the web page interface and a database of ontology terms. We currently store 40 of the ontologies from the OBO website 1, as well as a several others. These ontologies are automatically updated on a weekly basis. OntologyWidget can be used in any web-based application to take advantage of the ontologies we provide via web services or any other ontology that is provided elsewhere in the correct format. The full source code for the JavaScript and description of the OntologyWidget is available from http://smd.stanford.edu/ontologyWidget/.
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    Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.
    (Science (New York, N.Y.), 2020-12) Warren, Wesley C; Harris, R Alan; Haukness, Marina; Fiddes, Ian T; Murali, Shwetha C; Fernandes, Jason; Fernandes, Jason; Dishuck, Philip C; Storer, Jessica M; Raveendran, Muthuswamy; Hillier, LaDeana W; Porubsky, David; Mao, Yafei; Gordon, David; Vollger, Mitchell R; Lewis, Alexandra P; Munson, Katherine M; DeVogelaere, Elizabeth; Armstrong, Joel; Diekhans, Mark; Walker, Jerilyn A; Tomlinson, Chad; Graves-Lindsay, Tina A; Kremitzki, Milinn; Salama, Sofie R; Audano, Peter A; Escalona, Merly; Maurer, Nicholas W; Antonacci, Francesca; Mercuri, Ludovica; Maggiolini, Flavia AM; Catacchio, Claudia Rita; Underwood, Jason G; O'Connor, David H; Sanders, Ashley D; Korbel, Jan O; Ferguson, Betsy; Kubisch, H Michael; Picker, Louis; Kalin, Ned H; Rosene, Douglas; Levine, Jon; Abbott, David H; Gray, Stanton B; Sanchez, Mar M; Kovacs-Balint, Zsofia A; Kemnitz, Joseph W; Thomasy, Sara M; Roberts, Jeffrey A; Kinnally, Erin L; Capitanio, John P; Skene, JH Pate; Platt, Michael; Cole, Shelley A; Green, Richard E; Ventura, Mario; Wiseman, Roger W; Paten, Benedict; Batzer, Mark A; Rogers, Jeffrey; Eichler, Evan E
    The rhesus macaque (Macaca mulatta) is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.