James B. Jaynes, Ph.D.


Associate Professor
Biochemistry &Molecular Biology

Homeodomain Transcription Factors in Development

Telephone
215-503-4778

Office Address
479A Jefferson Alumni Hall
1020 Locust Street, Philadelphia, PA 19107

Email Address
J_Jaynes@mail.jci.tju.edu

 

Embryos regulate their growth and development in many ways, but control of gene transcription is particularly important for directing cells along particular 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 others expression, and subsequently instruct the rest of the genome in a manner appropriate to each position in the organism.  These regulatory proteins are conserved across the evolutionary distance separating flies and humans.  This applies to both their primary structure, implying similarity in mechanism, and often their developmental function.  That is, the regulatory scheme in which they function solves a common problem of developing multi-cellular organisms.  Our current studies revolve around understanding specific mechanisms of two types:  first, which gene products interact directly with which genes and other gene products, and second, how this impinges o­n transcriptional regulation and, relatedly, the stability of the epigenome.

My laboratory focuses on the regulation and function of two homeodomain-containing proteins.  The homeodomain is a highly conserved sequence-specific DNA binding domain found in transcriptional regulators from yeast to humans.  One of these, Engrailed (En), is a potent repressor of transcription that recruits the corepressor Groucho, a homolog of the TLE family of mammalian cofactors.  We are currently studying interactions between En and the Pbx and Meis/PREP families of Hox protein cofactors, which serve to increase its DNA-binding specificity and thereby direct it to particular target genes.  The interaction with En confers a novel activity o­n the Meis/PREP-Pbx complex (in Drosophila, Hth-Exd), that of transcriptional repression.  Our analysis focuses o­n the biochemical interactions among these factors, and o­n the functional consequences of altering those interactions.

Even-skipped (Eve) is another transcription factor that regulates developmental processes in a highly conserved fashion.  Eve, like En, uses both Groucho-dependent and independent mechanisms to repress transcription.  With the even-skipped gene (eve), we have the ability to completely rescue null mutants with a transgene, allowing us to functionally replace the endogenous gene.  This facilitates our studies of its regulation in vivo.  Currently, we are 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, and to maintain both the activated and repressed state within different developing lineages of cells.  These activities are mediated by an
insulator and a Polycomb-group response element.  Both of these kinds of elements function in a variety of genes, and in mammals as well as in
Drosophila, to regulate developmental processes like stem cell maintenance and differentiation.  Understanding the underlying mechanisms will provide novel ways to attack problems like cancer, which is caused in part by misregulation of gene expression and chromatin
structure.


Keywords: epigenetics, Polycomb group; insulator; transcription factor, development, Drosophila, homeodomain, repressor
 

PubMed Link For Jaynes JB


Selected Publications

Miki Fujioka, Xian Wu, and James B. Jaynes  (2009).  A chromatin insulator mediates transgene homing and very long-range enhancer-promoter communication.  Development 136: 3077-3087. http://dev.biologists.org/cgi/content/full/develop;136/18/3077

Miki Fujioka, Galina L. Yusibova, Jian Zhou, and James B. Jaynes  (2008).  The DNA binding Polycomb-group protein Pleiohomeotic maintains both active and repressed transcriptional states through a single site.  Development 135: 4131-4139. http://dev.biologists.org/cgi/content/full/135/24/4131

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 DrosophilaCell 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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