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| b>Research Interests The primary focus of my laboratory is on mechanisms of gene regulation. Embryos regulate their growth and development in many ways, but control of gene transcription is particularly important for directing cells along different developmental pathways. In Drosophila, a cascade of nuclear regulatory events establishes very early differences in cell fates by producing intricate patterns of gene expression. Many of these pattern-forming genes encode DNA binding proteins that regulate each other’s expression, and subsequently instruct the rest of the genome in a manner appropriate to each position in the organism. Recent work has shown that these regulatory proteins are conserved across the evolutionary distance separating flies and humans, both in terms of primary structure, implying similarity in mechanism, and, quite often, in terms of their developmental “meaning”; that is, how the regulatory scheme in which they function solves the common problems of a developing multi-cellular organism. Therefore, a detailed understanding of the interactions of conserved regulators in one system has important implications for their homologs in other systems. Questions addressed by current studies of embryogenesis revolve around understanding specific mechanisms of two types. First, which gene products interact directly with which other genes or gene products, and second, what are the molecular consequences of those interactions. My laboratory seeks an understanding of such mechanisms by focusing on the interactions and functions of two homeodomain-containing transcriptional regulators. One, Engrailed (En), is a potent active repressor both in cultured cells and in embryos. Using a novel in vivo assay, we identified a conserved repression domain that is shared among several other homeodomain and forkhead domain subfamilies. We found that it interacts with the corepressor Groucho, a homolog of the TLE family of mammalian cofactors, and we are investigating the functional consequences of this interaction. We are also studying interactions between En and the Pbx and Meis1 families of Hox protein cofactors, which we have shown interact functionally with En. This interaction confers a novel activity on the Meis1-Pbx complex (in Drosophila, Hth-Exd), that of transcriptional repression. This has important implications for the functions of En in specifying posterior vs. anterior compartment cell fates during development. Also, as some Meis-Pbx-Hox complexes are activators of transcription, the ability of En to counter that activity may be useful in a therapeutic context, such as to reverse the effects of Meis1 and Hox overexpression in promoting leukemia. We have also identified other En interacting proteins that are likely to be involved in the regulation of transcription. Future analysis will focus on the biochemical interactions among these factors, and on the functional consequences of altering those interactions. Even-skipped (Eve) is a second homeodomain transcription factor that regulates developmental processes in a highly conserved fashion. We have shown that Eve, like En, uses both Groucho-dependent and –independent mechanisms to repress transcription. With Eve, we have the ability to completely rescue null mutants with a transgene, allowing us to functionally replace endogenous Eve with altered proteins during development. In addition, we have constructed tissue-specific mutants by manipulating regulatory regions of the rescuing transgene. This allows us to dissect protein function independently in different tissues. We are also continuing to study the regulation of the even-skipped gene (eve). Currently, we are in the process of analyzing how long-range repression and activation occur over an entire genetic locus, through the regulation of chromatin structure. Included in the long-range regulatory elements of eve are a boundary region that helps to functionally isolate it from neighboring genes. Understanding the mechanisms of these kinds of processes will provide novel ways to approach problems such as cancer, which is caused in part by misregulation of gene expression and chromatin structure. Keywords: transcription factor, development, Drosophila, homeodomain, repressor | ||||
| Selected Publications Farhan Khan*, Miki Fujioka*, Pinaki Datta*, Teresa Fernandes-Alnemri, James B. Jaynes, and Emad S. Alnemri (2008). The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila; Cell Death and Differentiation 15: 1073-1083. *These authors contributed equally to the work. http://www.nature.com/cdd/journal/v15/n6/abs/cdd200819a.html Petruk, S., Sedkov, Y., Riley, K. M., Hodgson, J., Schweisguth, F., Hirose, S., Jaynes, J. B., Brock, H. W., and Mazo, A. (2006).Transcription of bxd non-coding RNAs promoted by Trithorax represses Ubx in cis by transcriptional interference; Cell 127: 1209-1221. Fujioka, M., Wessells,R.J., Han, Z., Liu, J., Fitzgerald, K., Yusibova, G.L., Zamora, M.,Ruiz-Lozano, P., Bodmer, R., and Jaynes, J.B. (2005). Embryonic even skipped-dependent muscle andheart cell fates are required for normal adult activity, heart function, andlifespan; Circ. Res. 97: 1108-1114. http://circres.ahajournals.org/cgi/content/full/01.RES.0000191546.08532.B2?ijkey=bYfjV61Jgd8UJzg&keytype=ref Jaynes JB, Fujioka M. Drawing lines in the sand: even skipped et al. and parasegment boundaries. Dev Biol 2004 May 15;269(2):609-22. ( Abstract ) Fujioka M, Lear BC, Landgraf M, Yusibova GL, Zhou J, Riley KM, Patel NH, Jaynes JB. Even-skipped, acting as a repressor, regulates axonal projections in Drosophila. Development 2003 Nov;130(22):5385-400. Epub 2003 Sep 16. ( Abstract ) Kobayashi M, Fujioka M, Tolkunova EN, Deka D, Abu-Shaar M, Mann RS, Jaynes JB. Engrailed cooperates with extradenticle and homothorax to repress target genes in Drosophila. Development 2003 Feb;130(4):741-51. ( Abstract ) Sedkov Y, Cho E, Petruk S, Cherbas L, Smith ST, Jones RS, Cherbas P, Canaani E, Jaynes JB, Mazo A. Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila. Nature 2003 Nov 6;426(6962):78-83. ( Abstract ) Landgraf M, Jeffrey V, Fujioka M, Jaynes JB, Bate M. Embryonic origins of a motor system: motor dendrites form a myotopic map in Drosophila. PLoS Biol 2003 Nov;1(2):E41. Epub 2003 Nov 17. ( Abstract ) McDonald JA, Fujioka M, Odden JP, Jaynes JB, Doe CQ. Specification of motoneuron fate in Drosophila: integration of positive and negative transcription factor inputs by a minimal eve enhancer. J Neurobiol 2003 Nov;57(2):193-203. ( Abstract ) Fujioka M, Yusibova GL, Patel NH, Brown SJ, Jaynes JB. The repressor activity of Even-skipped is highly conserved, and is sufficient to activate engrailed and to regulate both the spacing and stability of parasegment boundaries. Development 2002 Oct;129(19):4411-21. ( Abstract ) Han Z, Fujioka M, Su M, Liu M, Jaynes JB, Bodmer R. Transcriptional integration of competence modulated by mutual repression generates cell-type specificity within the cardiogenic mesoderm. Dev Biol 2002 Dec 15;252(2):225-40. ( Abstract ) Srinivasula SM, Datta P, Kobayashi M, Wu JW, Fujioka M, Hegde R, Zhang Z, Mukattash R, Fernandes-Alnemri T, Shi Y, Jaynes JB, Alnemri ES. sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein. Curr Biol 2002 Jan 22;12(2):125-30. ( Abstract ) Americo J, Whiteley M, Brown JL, Fujioka M, Jaynes JB, Kassis JA. A complex array of DNA-binding proteins required for pairing-sensitive silencing by a polycomb group response element from the Drosophila engrailed gene. Genetics 2002 Apr;160(4):1561-71. ( Abstract ) Kobayashi, M., Goldstein, R.E., Fujioka, M., Paroush, Z., and Jaynes, J.B. (2001). Groucho augments the repression of multiple Even-skipped target genes in establishing parasegment boundaries, Development 128: 1805-1815. Zhu W, Foehr M, Jaynes JB, Hanes SD. Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex interacts with Bicoid and inhibits its activity. Dev Genes Evol 2001 Mar;211(3):109-17. ( Abstract ) Park Y, Fujioka M, Kobayashi M, Jaynes JB, Datta S. even skipped is required to produce a trans-acting signal for larval neuroblast proliferation that can be mimicked by ecdysone. Development 2001 May;128(10):1899-909. ( Abstract ) Fujioka M, Jaynes JB, Bejsovec A, Weir M. Production of transgenic Drosophila. Methods Mol Biol 2000;136:353-63. ( Abstract ) Hosoya T, Hiromi Y, Fujioka M, Jaynes JB. [Developmental regulation by Drosophila Runt-domain proteins Runt and Lozenge. Tanpakushitsu Kakusan Koso 2000 Jan;45(1):7-12. ( Abstract ) Fujioka M, Emi-Sarker Y, Yusibova GL, Goto T, Jaynes JB. Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients. Development 1999 Jun;126(11):2527-38. ( Abstract ) Baines RA, Robinson SG, Fujioka M, Jaynes JB, Bate M. Postsynaptic expression of tetanus toxin light chain blocks synaptogenesis in Drosophila. Curr Biol 1999 Nov 4;9(21):1267-70. ( Abstract ) Tolkunova EN, Fujioka M, Kobayashi M, Deka D, Jaynes JB. Two distinct types of repression domain in engrailed: one interacts with the groucho corepressor and is preferentially active on integrated target genes. Mol Cell Biol 1998 May;18(5):2804-14. ( Abstract ) Park Y, Fujioka M, Jaynes JB, Datta S. Drosophila homeobox gene eve enhances trol, an activator of neuroblast proliferation in the larval CNS. Dev Genet 1998;23(3):247-57. ( Abstract ) Smith ST, Jaynes JB. A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development 1996 Oct;122(10):3141-50. ( Abstract ) | ||||
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