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    Scot Wolfe PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-619
    Worcester MA 01605
    Phone508-856-3953
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentProgram in Molecular Medicine

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBioinformatics and Computational Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentChemical Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Gene Function and Expression

        Overview 
        Narrative

        Academic Background

        Scot Wolfe received his B.S. in Chemistry and Biology from Caltech in 1990, and his Ph.D. from Harvard in Chemistry in 1996. From 1996-2001 he was a post-doctoral fellow at Massachusetts Institute of Technology where his work was supported in part by the Leukemia and Lymphoma Society. In 2001, Dr. Wolfe joined the faculty of UMMS.

        Creating Artifical DNA-Binding Domains for Targeted Gene Regulation and Gene Modification

        Scot Wolfe My research program is focused on three inter-related areas:

        • Understanding fundamental aspects of protein-DNA recognition
        • Engineering artificial transcription factors for targeted gene regulation and modification
        • Developing selection technologies to characterize and engineer protein-DNA interactions
        Protein-DNA recognition - Our research on protein-DNA recognition is focused primarily on two of the most abundant families of DNA-binding domains in metazoans (see our lab website for more detailslabs.umassmed.edu/WolfeLab ):

        Cys2His2 Zinc fingers & Homeodomains

        We have recently performed the first comprehensive analysis of homeodomain specificities in a metazoan (D. melanogaster – fruit fly) in collaboration withMichael Brodsky(UMMS-PGFE) &Gary Stormo(Wash. U) (Noyes et al., Cell 2008). Using this information we can build simple qualitative models of recognition that allow the design of homeodomains with novel DNA-binding specificity. This dataset can also be used to broadly predict the specificity of family members from other species (seeural.wustl.edu/flyhd). We continue to build upon this work to understand fundamental aspects of DNA-recognition for the homeodomain and zinc finger families with the goal of broadly and accurately predicting the specificity of naturally-occurring family members in all species. These studies will also provide a valuable resource for understanding specificity determinants within each family for rationally engineering the specificity of these DNA-binding domains.
        B1H selection systems - We continue to develop a bacterial one-hybrid system for rapidly characterizing the DNA-binding specificities of sequence-specific transcription factors, both naturally-occurring and engineered. Using this technology we intend to characterize all of the sequence-specific transcription factors in the D. melanogaster genome in collaboration with the laboratory ofMichael Brodsky(UMMS – PGFE). This dataset will be used to unravel transcription factor regulatory networks within the fly in collaboration withSaurabh Sinha(UI-Urbana Champaign). We have already begun building computational tools to allow the scientific community to identify cis-regulatory modules using clusters of phylogenetically conserved binding sites for the ~15% of the TFs in the fly genome that we have characterized to date (GenomeSurveyor -biotools.umassmed.edu/genomesurveyor).
        ZFNs in Zebrafish - We have utilized our selection technology to create zinc finger nucleases that recognize specific genes in the Zebrafish genome in collaboration withNathan Lawson(UMMS – PGFE). Zinc finger nucleases (ZFNs) are tailor-made restriction endonucleases that can generate a double-stranded break at a specific DNA sequence defined by the specificity of the attached zinc fingers. Using this technology we have made the first targeted gene knockouts in the zebrafish (Meng et al., Nat. Biotech 2008). We continue to develop these DNA-targeting and cleavage tools with the goal of creating an accessible resource for model organism communities that will allow them to disrupt, or modify, a desired gene in any model organism. This technology should revolutionize reverse genetic approaches in most model organisms and may allow the straightforward creation of tailor-made human disease models with profound implications for the development of treatments for a variety of diseases.



        Rotation Projects

        Potential Rotation Projects

        Optimization of the Zinc Finger Nuclease framework and the creation of disease models in zebrafish:

        Zinc finger nucleases hold tremendous potential for site-specifically editing genomes in a variety of organisms. Their utility, however, is predicated on the ability to efficiently create sequence-specific zinc finger proteins (ZFPs) for a wide variety of target sequences. My laboratory is focused on the creation of improved zinc finger modules for DNA recognition, improved chimeric frameworks to broadennuclease activity, and the application of these artificial nucleases to construct disease models in zebrafish.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Gupta A, Hall VL, Kok FO, Shin M, McNulty JC, Lawson ND, Wolfe SA. Targeted chromosomal deletions and inversions in zebrafish. Genome Res. 2013 Jun; 23(6):1008-17.
          View in: PubMed
        2. Enuameh MS, Asriyan Y, Richards A, Christensen RG, Hall VL, Kazemian M, Zhu C, Pham H, Cheng Q, Blatti C, Brasefield JA, Basciotta MD, Ou J, McNulty JC, Zhu LJ, Celniker SE, Sinha S, Stormo GD, Brodsky MH, Wolfe SA. Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants. Genome Res. 2013 Jun; 23(6):928-40.
          View in: PubMed
        3. Zhu C, Gupta A, Hall VL, Rayla AL, Christensen RG, Dake B, Lakshmanan A, Kuperwasser C, Stormo GD, Wolfe SA. Using defined finger-finger interfaces as units of assembly for constructing zinc-finger nucleases. Nucleic Acids Res. 2013 Feb 1; 41(4):2455-65.
          View in: PubMed
        4. Merlin C, Beaver LE, Taylor OR, Wolfe SA, Reppert SM. Efficient targeted mutagenesis in the monarch butterfly using zinc-finger nucleases. Genome Res. 2013 Jan; 23(1):159-68.
          View in: PubMed
        5. Anderson DM, George R, Noyes MB, Rowton M, Liu W, Jiang R, Wolfe SA, Wilson-Rawls J, Rawls A. Characterization of the DNA-binding Properties of the Mohawk Homeobox Transcription Factor. J Biol Chem. 2012 Oct 12; 287(42):35351-9.
          View in: PubMed
        6. Shin J, Padmanabhan A, de Groh ED, Lee JS, Haidar S, Dahlberg S, Guo F, He S, Wolman MA, Granato M, Lawson ND, Wolfe SA, Kim SH, Solnica-Krezel L, Kanki JP, Ligon KL, Epstein JA, Look AT. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Dis Model Mech. 2012 Nov; 5(6):881-94.
          View in: PubMed
        7. Christensen RG, Enuameh MS, Noyes MB, Brodsky MH, Wolfe SA, Stormo GD. Recognition models to predict DNA-binding specificities of homeodomain proteins. Bioinformatics. 2012 Jun 15; 28(12):i84-i89.
          View in: PubMed
        8. Gupta A, Christensen RG, Rayla AL, Lakshmanan A, Stormo GD, Wolfe SA. An optimized two-finger archive for ZFN-mediated gene targeting. Nat Methods. 2012 Apr 29; 9(6):588-90.
          View in: PubMed
        9. Chu SW, Noyes MB, Christensen RG, Pierce BG, Zhu LJ, Weng Z, Stormo GD, Wolfe SA. Exploring the DNA-recognition potential of homeodomains. Genome Res. 2012 Apr 26.
          View in: PubMed
        10. Zhu C, Smith T, McNulty J, Rayla AL, Lakshmanan A, Siekmann AF, Buffardi M, Meng X, Shin J, Padmanabhan A, Cifuentes D, Giraldez AJ, Look AT, Epstein JA, Lawson ND, Wolfe SA. Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish. Development. 2011 Oct; 138(20):4555-64.
          View in: PubMed
        11. Lawson ND, Wolfe SA. Forward and reverse genetic approaches for the analysis of vertebrate development in the zebrafish. Dev Cell. 2011 Jul 19; 21(1):48-64.
          View in: PubMed
        12. Christensen RG, Gupta A, Zuo Z, Schriefer LA, Wolfe SA, Stormo GD. A modified bacterial one-hybrid system yields improved quantitative models of transcription factor specificity. Nucleic Acids Res. 2011 Jul 1; 39(12):e83.
          View in: PubMed
        13. Bussmann J, Wolfe SA, Siekmann AF. Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling. Development. 2011 May; 138(9):1717-26.
          View in: PubMed
        14. Zhu LJ, Christensen RG, Kazemian M, Hull CJ, Enuameh MS, Basciotta MD, Brasefield JA, Zhu C, Asriyan Y, Lapointe DS, Sinha S, Wolfe SA, Brodsky MH. FlyFactorSurvey: a database of Drosophila transcription factor binding specificities determined using the bacterial one-hybrid system. Nucleic Acids Res. 2011 Jan; 39(Database issue):D111-7.
          View in: PubMed
        15. Gupta A, Meng X, Zhu LJ, Lawson ND, Wolfe SA. Zinc finger protein-dependent and -independent contributions to the in vivo off-target activity of zinc finger nucleases. Nucleic Acids Res. 2011 Jan 1; 39(1):381-92.
          View in: PubMed
        16. Kazemian M, Blatti C, Richards A, McCutchan M, Wakabayashi-Ito N, Hammonds AS, Celniker SE, Kumar S, Wolfe SA, Brodsky MH, Sinha S. Quantitative analysis of the Drosophila segmentation regulatory network using pattern generating potentials. PLoS Biol. 2010; 8(8).
          View in: PubMed
        17. Cifuentes D, Xue H, Taylor DW, Patnode H, Mishima Y, Cheloufi S, Ma E, Mane S, Hannon GJ, Lawson ND, Wolfe SA, Giraldez AJ. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science. 2010 Jun 25; 328(5986):1694-8.
          View in: PubMed
        18. Siekmann AF, Standley C, Fogarty KE, Wolfe SA, Lawson ND. Chemokine signaling guides regional patterning of the first embryonic artery. Genes Dev. 2009 Oct 1; 23(19):2272-7.
          View in: PubMed
        19. Noyes MB, Christensen RG, Wakabayashi A, Stormo GD, Brodsky MH, Wolfe SA. Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell. 2008 Jun 27; 133(7):1277-89.
          View in: PubMed
        20. Meng X, Noyes MB, Zhu LJ, Lawson ND, Wolfe SA. Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nat Biotechnol. 2008 Jun; 26(6):695-701.
          View in: PubMed
        21. Noyes MB, Meng X, Wakabayashi A, Sinha S, Brodsky MH, Wolfe SA. A systematic characterization of factors that regulate Drosophila segmentation via a bacterial one-hybrid system. Nucleic Acids Res. 2008 May; 36(8):2547-60.
          View in: PubMed
        22. Meng X, Thibodeau-Beganny S, Jiang T, Joung JK, Wolfe SA. Profiling the DNA-binding specificities of engineered Cys2His2 zinc finger domains using a rapid cell-based method. Nucleic Acids Res. 2007; 35(11):e81.
          View in: PubMed
        23. Meng X, Smith RM, Giesecke AV, Joung JK, Wolfe SA. Counter-selectable marker for bacterial-based interaction trap systems. Biotechniques. 2006 Feb; 40(2):179-84.
          View in: PubMed
        24. Meng X, Wolfe SA. Identifying DNA sequences recognized by a transcription factor using a bacterial one-hybrid system. Nat Protoc. 2006; 1(1):30-45.
          View in: PubMed
        25. Meng X, Brodsky MH, Wolfe SA. A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors. Nat Biotechnol. 2005 Aug; 23(8):988-94.
          View in: PubMed
        26. Wolfe SA. Mapping key elements of a protein motif. Chem Biol. 2004 Jul; 11(7):889-91.
          View in: PubMed
        27. Wolfe SA, Grant RA, Pabo CO. Structure of a designed dimeric zinc finger protein bound to DNA. Biochemistry. 2003 Nov 25; 42(46):13401-9.
          View in: PubMed
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