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Staff Scientist

Thomas Brody, Ph.D.


Building 35 Room 1B1016
35 Convent Drive
Bethesda 20892
Office: 301-496-8409

Fax: 301-402-0245
brodyt@ninds.nih.gov



Identification of the cis-regulatory elements that control coordinate gene expression is one of the longstanding goals of molecular biology. We have developed an integrated methodology and accompanying algorithms, including EvoPrinter and a suite of web-accessed search algorithms, cis-Decoder, that identifies functionally related cis-regulatory enhancers. For this analysis we have generated a Drosophila genome-wide database of conserved DNA consisting of greater than 100,000 conserved sequence clusters (CSCs) derived from EvoPrints spanning over 90% of the genome. cis-Decoder first identifies conserved repeat elements within an input enhancer and then searches the database for CSCs that score highly against the input CSC. Scoring is based on shared repeats as well as uniquely shared matches, and includes measures of the balance of shared elements, a diagnostic that has proven to be useful in predicting cis-regulatory function. 

To demonstrate the utility of these tools, a temporally-restricted CNS neuroblast enhancer, characterized in our analysis of regulation of the temporal determinant castor, was used to identify other functionally related enhancers and analyze their structural organization.cis-Decoder reveals that co-regulating enhancers consist of combinations of overlapping shared sequence elements, providing insights into the mode of integration of multiple regulating transcription factors. The database and accompanying algorithms should prove useful in the discovery and analysis of enhancers involved in any developmental process.

For the last seventeen years I have maintained the Web resource entitled The Interactive Fly: A Cyberspace Guide to Drosophila Development and metazoan evolution. Drosophila is a good starting place from which to design an interactive model of development, and cyberspace is the made-to-order medium. The Interactive Fly is used at every level of study, including high school, college, graduate school and as a reference for researchers. It has also been used by programmers to develop methods of machine reading of biology text.



Identification of novel embryonic neural precursor cell enhancers based on shared repeat sequences

brody

cis-Decoder database searches using conserved sequences of the castor late temporal network enhancer (cas-6) identified other enhancers that share balanced repeat sequences with the cas-6 enhancer. These structurally similar enhancers also function as late NB sub-lineage enhancers. Many identified CSCs are adjacent to known NB expressed genes (vvl, nab, cas, tkr, and grh).

Although the cas-6-related enhancers are active in overlapping neural precursor cells, each has its own unique cis-regulatory identity. Each has a different pattern of expression in subsets of NBs, GMCs, and/or nascent neurons. For example, three identified enhancers (nab-1, CG6559-28, and tkr-15) exhibit early expression in a subset of ventral cord midline cells, while other enhancers do not activate reporter expression in the midline precursor cells. The cas-8 CSC activated reporter expression in many more precursors at stage 11 than any of the other reporter constructs. tkr-15 is expressed in many cells at stage 11. Since these cells are too small to be considered NBs, they are most likely GMCs or nascent neurons. cas-6 and cas-8 enhancers both drive reporter expression in overlapping subsets of cells that represent sub-patterns of endogenouscas expression.

Our studies also revealed that there is no apparent consistency in the ordering, overlap, or orientation of shared elements between functionally related enhancers. For example, repeat and palindromic elements shared between cas-6, cg7229-5, and grh-15 appear in unique contexts within each enhancer.

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  • 1) Brody T, Yavatkar AS, Kuzin A, Kundu M, Tyson LJ, Ross J, Lin TY, Lee CH, Awasaki T, Lee T, Odenwald WF. (2012)
  • Use of a Drosophila genome-wide conserved sequence database to identify functionally related cis-regulatory enhancers
  • Dev Dyn. , 241(1), 169-89
  • 2) Kuzin, A., Kundu, M., Ross, J., Koizum,i K., Brody, T. and Odenwald, W.F. (2012)
  • The cis-regulatory dynamics of the Drosophila CNS determinant castor are controlled by multiple sub-pattern enhancers
  • Gene Expression Patterns 9, 12(7-8), 261-272
  • 3) Kuzin A, Kundu M, Brody T, Odenwald WF (2011)
  • Functional analysis of conserved sequences within a temporally restricted neural precursor cell enhancer.
  • Neural Cell-Fate Determinants Section
  • 4) Kuzin A, Kundu M, Ekatomatis A, Brody T, Odenwald WF (2009)
  • Conserved sequence block clustering and flanking inter-cluster flexibility delineate enhancers that regulate nerfin-1 expression during Drosophila CNS development.
  • Gene Expr Patterns, 9, 65-72
  • 5) Brody T, Rasband W, Baler K, Kuzin A, Kundu M, Odenwald WF. (2008)
  • Sequence conservation and combinatorial complexity of Drosophila neural precursor cell enhancers
  • BMC Genomics, 9, 371
  • 6) Brody T, Yavatkar AS, Lin Y, Ross J, Kuzin A, Kundu M, Fann Y, Odenwald WF. (2008)
  • Horizontal gene transfers link a human MRSA pathogen to contagious bovine mastitis bacteria.
  • PLoS One, 3, e3074
  • 7) Yavatkar AS, Lin Y, Ross J, Fann Y, Brody T, Odenwald WF. (2008)
  • Rapid detection and curation of conserved DNA via enhanced-BLAT and EvoPrinterHD analysis.
  • BMC Genomics , 9, 106
  • 8) Brody T, Rasband W, Baler K, Kuzin A, Kundu M, Odenwald WF. (2007)
  • cis-Decoder discovers constellations of conserved DNA sequences shared among tissue-specific enhancers.
  • Genome Biol. , 8(5), R7
  • 9) Kuzin A, Kundu M, Brody T, Odenwald WF (2007)
  • The Drosophila nerfin-1 mRNA requires multiple microRNAs to regulate its spatial and temporal translation dynamics in the developing nervous system.
  • Dev Biol., 310, 35-43
  • 10) Kuzin A, Brody T, Moore AW, Odenwald WF (2005)
  • Nerfin-1 is required for early axon guidance decisions in the developing Drosophila CNS
  • Dev Biol, 277, 347-65
  • 11) Odenwald WF, Rasband W, Kuzin A, Brody T (2005)
  • EVOPRINTER, a multigenomic comparative tool for rapid identification of functionally important DNA
  • Proc Natl Acad Sci , 102, 14700-5
  • 12) Brody T, Odenwald WF (2005)
  • Regulation of temporal identities during Drosophila neuroblast lineage development
  • Curr Opin Cell Biol, 17, 672-5
  • 13) Brody T, Odenwald WF. (2002)
  • Cellular diversity in the developing nervous system: A temporal view from Drosophila
  • Development, 129, 3763-70
  • 14) Brody, T., Stivers, C., Nagle, J., and Odenwald, W. F. (2002)
  • Identification of Novel Drosophila Neural Precursor Genes
  • Mech. Dev., 113, 41-59
  • 15) Brody T, Koizumi K, Stivers C, Zangeneh S, Mozer B, Odenwald WF. (2001)
  • A search for Drosophila neural precursor genes identifies ran.
  • Dev Genes Evol., 211, 67-75
  • 16) Stivers C, Brody T, Kuzin A, Odenwald WF. (2000)
  • Nerfin-1 and -2, novel Drosophila Zn-finger transcription factor genes expressed in the developing nervous system.
  • Mech. Dev., 97, 205-10
  • 17) Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, Fortini ME, Li PW, Apweiler R, Fleischmann W, Cherry JM, Henikoff S, Skupski MP, Misra S, Ashburner M, Birney E, Boguski MS, Brody T, Brokstein P, Celniker SE, Chervitz SA, Coates D, Cravchik A, Gabrielian A, Galle RF, Gelbart WM, George RA, Goldstein LS, Gong F, Guan P, Harris NL, Hay BA, Hoskins RA, Li J, Li Z, Hynes R (2000)
  • Comparative genomics of the eukaryotes.
  • Science, 287, 2204-15
  • 18) Brody T, Cravchik A. (2000)
  • Drosophila melanogaster G protein-coupled receptors.
  • J Cell Biol, 150, F83-8
  • 19) Brody T, Odenwald WF. (2000)
  • Programmed transformations in neuroblast gene expression during Drosophila CNS lineage development.
  • Dev. Biol., 226, 34-44.
  • 20) Brody, T. (1999)
  • The Interactive Fly: gene networks, development and the internet
  • Trends Genet. , 15, 333-4
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