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Jef Boeke Photo

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Jef Boeke - Professor
Molecular Biology & Genetics

733 N. Broadway
339 MRB
Baltimore, MD 21205

Office: 410-955-2481
Fax: 410-502-1872

jboeke@jhmi.edu

Assistant:
Transposition, yeast genetics, and “omics” technology
Our group is focused on the mobile elements called retrotransposons that infest the genomes of all eukaryotes. We study their mechanism of movement (retrotransposition) and how they find their homes in host genomes. Most of our work is centered on the Ty1 elements of yeast and on the human L1 (LINE) elements. The Ty1 elements greatly resemble retroviruses but have one unique and interesting feature: they target very specific "windows" in the yeast genomes as sites of integration. We believe this targeting is dictated by a chromatin structure unique to these regions and are investigating the molecular mechanisms involved. In addition, because Ty1’s host is the highly genetically amenable yeast Saccharomyces cerevisiae, it is possible to carry out detailed molecular genetic analyses of the complex steps in the retrotransposition pathway, both in analyzing the transposon itself and host-encoded functions. L1s are responsible, directly or indirectly for over a third of our genome by weight. The human L1 element also transposes via reverse transcription, but it looks and behaves very differently from Ty1 and retroviruses. Integral to its insertion mechanism is an unusual DNA repair-like endonuclease that is not found in retroviral-like elements. We tackle retrotransposition mechanism and its regulation of retrotransposition at several levels - genetic, molecular, biochemical, systems/bioinformatic and more recently by redesign and synthesis of the elements. These comparative studies help define core conserved reactions of retrotransposition as well as highlighting retroelement diversity. We have also developing methods to profile transposons genome-wide in human individual to explore how significant retrotransposon movement is in natural populations and to what extent it underlies phenotypic differences.

Our work on retrotransposons led us to studies of transcriptional silencing. The Sir2 protein is a member of a phylogenetically conserved family of NAD-dependent protein (lysine) deacetylases. Interest in this unusual family of proteins has expanded to a general interest in the myriad connections between lysine modifications and biology. We also partner with colleagues in the HiT Center to develop new technology and analyze large datasets.  One tool we’ve developed to study global genetic interactions is called SLAM, (Synthetic Lethality Analyzed by Microarray). Another important tool is protein microarrays, which can be used to identify targets of acetyltranferases.  These and other “Omics” tools, can help assemble biological networks and organize them into pathways. Together with many colleagues at JHU and elsewhere, this has led a large project to better understand the networks and pathways or lysine modification. We are fortunate to be supported in this by an NIH Roadmap “National Technology Center for Networks & Pathways”.

Our studies of synthetic retrotransposons led us to consider redesigning and synthesizing entire eukaryotic chromosomes and even a remodeled Saccharomyces cerevisiae genome, Sc2.0. See http://syntheticyeast.org/ for more information. We are assisted in this by an army of undergraduates in the course “Build A Genome”, in which undergraduates synthesize the “Building Blocks” for the project while learning molecular biology and bioinformatics, as well as an international network of colleagues. Teams in China, the UK and elsewhere are synthesizing various chromosomes as part of this network.

Relevant Publications:
O’Donnell KA, An W, Schrum CT, Wheelan SW, Boeke JD. 2013. Controlled insertional mutagenesis using a LINE-1 (ORFeus) gene trap mouse model, Proc. Natl. Acad. Sci. USA, in press. 

Huang Q, Purzycka KJ, Lusvarghi S, Li D, LeGrice SFJ, Boeke JD 2013.  Retrotransposon Ty1 RNA contains a 5’ terminal long-range pseudoknot required for efficient reverse transcription.  RNA, 19:320-32. PubMed Reference

Mularoni L, Zhou Y, Bowen T, Gangadharan S,  Wheelan SJ and Boeke JD. 2012 Retrotransposon Ty1 integration targets specifically positioned asymmetric nucleosomal DNA segments in tRNA hotspots.  Genome Res., 22:693-703. PubMed Reference

Lu, JY, Lin, YY, Sheu, JC, Wu, JT, Lee, FJ, Lin, MI, Chiang, FT, Tai, TY, Zhao, Y, Berger, S., Tsai KS, Zhu, H., Chuang LM, Boeke JD. 2011. Acetylation of yeast AMP-activated protein kinase controls intrinsic aging independently of caloric restriction. Cell, 146:969-79. PubMed Reference

Dymond JS, Richardson S.M, Coombes CE, Müller H, Annaluru N, Blake WJ, Schwerzmann JW, Dai J, Lindstrom DL, Boeke AC, Gottschling D, Chandrasegaran S, Bader JS, and Boeke JD. 2011. Synthetic chromosome arms function in yeast and generate phenotypic diversity by design.  Nature, 477:471-476. PubMed Reference

Huang CRL, Schneider AM, Lu Y, Niranjan T, Shen P, Robinson, MA, Steranka, JP, Valle D, Civin CI, Wang T, Wheelan SJ, Ji HK, Boeke JD, Burns KH (2010) Mobile Interspersed repeats are major structural variants in the human genome. Cell 141: 1171-1182.  PubMed Reference

Lin, Y.Y., Lu, J.Y., Zhang, J., Walter, W., Wan, J., Tao, S.C., Qian, J., Zhao, Y., Boeke, J.D., Berger, S., Zhu, H. 2009. Protein acetylation microarray reveals NuA4 controls key chronologic aging target regulating gluconeogenesis. Cell 136:1073-84.  PubMed Reference

Dymond, J.S., Scheifele, L.Z., Richardson, S., Lee, P., Chandrasegaran, S., Bader, J.S., Boeke, J.D. (2009). Teaching synthetic biology, bioinformatics, and engineering to undergraduates: the interdisciplinary Build-a-Genome course. Genetics, 181: 13-21. PubMed Reference

Dai, J., Hyland, E.M., Yuan, D.S., Huang, H., Bader, J.S. and Boeke, J.D. 2008. Probing nucleosome function: A highly versatile library of synthetic histone H3 and H4 mutants. Cell 34:1066-78. PubMed Reference 

Wheelan S.J., Scheifele L.Z., Martinez-Murillo F., Irizarry R.A., Boeke J.D. (2006) Transposon insertion site profiling chip (TIP-chip). Proc Natl Acad Sci U S A 103:17632-17637.  PubMed Reference 

Pan, X., Ye, P., Yuan, D., Wang, X., Bader. J.S., Boeke J.D. (2006) The DNA integrity network in the yeast Saccharomyces cerevisiae. Cell 124: 1069-1081. PubMed Reference 

Richardson, S.M., Wheelan, S.J., Yarrington, R.M., Boeke, J.D. (2006) GeneDesign: Rapid, automated design of multikilobase synthetic genes. Genome Res. 16: 550-556.  PubMed Reference 

An W, Han JS, Wheelan S.J, Davis E, Coombes CE, Ye P, Triplett C, Boeke JD. (2006) Active retrotransposition by a synthetic mouse L1 element in mice. Proc. Natl. Acad. Sci. USA, 103:18662-7.  PubMed Reference 

Han, JS and Boeke JD. (2004) A highly active synthetic mammalian retrotransposon. Nature 429: 314-318.  PubMed Reference
 
Graduate Program AffiliationsHuman Genetics and Molecular Biology
Biochemistry, Cellular & Molecular Biology (BCMB)

 

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