Sign in to edit your profile (add interests, mentoring, photo, etc.)
    Keywords
    Last Name
    Institution

    Charles G Sagerstrom PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-8006
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

        B.A., Macalester College, MN, 1987
        Ph.D., Stanford University, CA, 1993

        Gene expression in embryogenesis

        Formation of the vertebrate central nervous system (CNS) begins early during embryogenesis - at gastrula stages, but extensive refinements continue to take place before the fully functional adult CNS emerges. Neural development is carefully controlled and perturbations of this process give rise to defects ranging from severe developmental abnormalities to mild cognitive impairments. We are studying genes that control early neural development, particularly formation of the caudal CNS (hindbrain and spinal cord) in the zebrafish, using a three-step strategy.

        Gene discovery
        We are screening for novel genes involved in neural development by several approaches. First, we have used subtractive hybridization to isolate genes expressed specifically in the caudal CNS. Second, we are using ‘expression profiling’ to identify novel genes expressed downstream of paralog group 1 hox genes in the caudal hindbrain. Third, we are undertaking a haploid genetic screen for mutations affecting hindbrain development.

        Derive genetic pathways
        We next integrate these genes into pathways that drive hindbrain development, using a number of molecular genetic approaches. For instance, we use injection of synthetic mRNA to ectopically activate gene function in wild type embryos, or to rescue defects in various mutant lines, and we use TALEN and CRISPR technology to ‘knock out’ the function of specific genes. In addition, we have recently adapted the Gal4:UAS transgenic system to achieve tissue specific expression of transgenes within the developing hindbrain.

        Define biochemical activities
        Lastly, we define the function of the various gene products using a variety of biochemical approaches. Since the majority of the genes we identified turn out to act as transcription factors (pbx4, meis3, hoxb1b, hoxb1a, nlz1, nlz2, prdm12), we have used ChIP to assay binding of these factors to target promoters in zebrafish embryos. Similarly, we have used ChIP to detect changes in histone modifications mediated by these transcription factors at specific promoters. Furthermore, several of the hindbrain specific genes we identified appear to act as protein phosphatases and we are currently attempting to identify their substrates both in zebrafish embryos and in cell culture systems.

        Research Figure

        Zebrafish Image

        Legend:

        Wholemount in situ hybridization detects the expressionof four different genes (two in red, two in black) in the formingneurectoderm of the zebrafish. (Dorsal view at 10 hours post fertilization.)



        Rotation Projects

        Rotation Project Background

        During early embryogenesis the primordium of the central nervous system (CNS) consists of an epithelium - the neural plate - that is only a single cell-layer thick. The neural plate subsequently undergoes an extraordinary set of developmental steps to form all structures of the adult CNS. This process raises two separate, but interrelated, questions: 1). How is each neural structure positioned correctly? and 2). How is the differentiation of each structure regulated? We are particularly interested in understanding the earliest steps in these processes and we focus our work on how the caudal CNS (the cerebellum, brainstem and spinal cord) is formed.

        We have isolated several genes that are expressed in the neural plate and we use zebrafish embryos to explore the role of these genes in formation of the caudal CNS. We combine in vivo experiments aimed at defining the biological role of each gene with in vitro biochemical experiments aimed at understanding their mechanism of action.

        Potential Rotation Projects

        1. Role of Meis and Pbx proteins in controlling histone modifications. Meis and Pbx proteins have been shown to act in complexes together with Hox proteins to regulate transcription. More recently, our ChIP experiments revealed that Meis and Pbx are bound at target promoters several hours prior to the binding of Hox proteins and well before the target gene becomes transcribed. Our preliminary experiments indicate that Meis and Pbx may act to control histone modifications at these early stages of embryogenesis, perhaps to permit subsequent binding of Hox proteins. This project entails the use of ChIP assays to determine whether histone modifications affect Hox binding, as well as to test whether binding of Hox proteins constitutes a 'switch' that initiates transcription of the target gene.
        2. Nucleosome positioning at hox promoters. Nucleosomes are involved in packaging genomic DNA, but also have regulatory functions as they can permit (or prevent) access of various DNA binding factors to genomic DNA. We have used micrococcal nuclease mapping to identify nucleosome occupancy at hox promoters during zebrafish embryogenesis. We find that nucleosomes may shift as hox transcription is initiated. This project involves assaying nucleosome occupancy in response to various stimuli, as well as determining whether shifts in nucleosome occupancy is a cause or an effect of transcription.
        3. Deriving a genetic pathway for the formation of hindbrain rhombomere (r) 4 and 5.  A number of genes are required for formation of r4 and r5, but it is not clear how they fit into a genetic pathway.  This project entails gene misexpression in wild type and mutant zebrafish embryos using mRNA injections and transgenic lines. In addition, it appears that several of these genes may encode protein phosphatases. An additional project therefore centers on identifying likely substrates of these phosphatases.


        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Sagerström for additional details.

        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Choe SK, Ladam F, Sagerström CG. TALE Factors Poise Promoters for Activation by Hox Proteins. Dev Cell. 2014 Jan 27; 28(2):203-11.
          View in: PubMed
        2. Ladam F, Sagerström CG. Hox regulation of transcription: More complex(es). Dev Dyn. 2014 Jan; 243(1):4-15.
          View in: PubMed
        3. Weicksel SE, Xu J, Sagerström CG. Dynamic nucleosome organization at hox promoters during zebrafish embryogenesis. PLoS One. 2013; 8(5):e63175.
          View in: PubMed
        4. Choe SK, Nakamura M, Ladam F, Etheridge L, Sagerström CG. A Gal4/UAS system for conditional transgene expression in rhombomere 4 of the zebrafish hindbrain. Dev Dyn. 2012 Jun; 241(6):1125-32.
          View in: PubMed
        5. Zannino DA, Sagerström CG, Appel B. olig2-Expressing hindbrain cells are required for migrating facial motor neurons. Dev Dyn. 2012 Feb; 241(2):315-26.
          View in: PubMed
        6. Choe SK, Zhang X, Hirsch N, Straubhaar J, Sagerström CG. A screen for hoxb1-regulated genes identifies ppp1r14al as a regulator of the rhombomere 4 Fgf-signaling center. Dev Biol. 2011 Oct 15; 358(2):356-67.
          View in: PubMed
        7. Mallappa C, Nasipak BT, Etheridge L, Androphy EJ, Jones SN, Sagerström CG, Ohkawa Y, Imbalzano AN. Myogenic microRNA expression requires ATP-dependent chromatin remodeling enzyme function. Mol Cell Biol. 2010 Jul; 30(13):3176-86.
          View in: PubMed
        8. Alexa K, Choe SK, Hirsch N, Etheridge L, Laver E, Sagerström CG. Maternal and zygotic aldh1a2 activity is required for pancreas development in zebrafish. PLoS One. 2009; 4(12):e8261.
          View in: PubMed
        9. Choe SK, Lu P, Nakamura M, Lee J, Sagerström CG. Meis cofactors control HDAC and CBP accessibility at Hox-regulated promoters during zebrafish embryogenesis. Dev Cell. 2009 Oct; 17(4):561-7.
          View in: PubMed
        10. Nakamura M, Choe SK, Runko AP, Gardner PD, Sagerström CG. Nlz1/Znf703 acts as a repressor of transcription. BMC Dev Biol. 2008; 8:108.
          View in: PubMed
        11. Choe SK, Hirsch N, Zhang X, Sagerström CG. hnf1b genes in zebrafish hindbrain development. Zebrafish. 2008 Sep; 5(3):179-87.
          View in: PubMed
        12. diIorio P, Alexa K, Choe SK, Etheridge L, Sagerström CG. TALE-family homeodomain proteins regulate endodermal sonic hedgehog expression and pattern the anterior endoderm. Dev Biol. 2007 Apr 1; 304(1):221-31.
          View in: PubMed
        13. Choe SK, Sagerström CG. Variable Meis-dependence among paralog group-1 Hox proteins. Biochem Biophys Res Commun. 2005 Jun 17; 331(4):1384-91.
          View in: PubMed
        14. Sagerström CG, Gammill LS, Veale R, Sive H. Specification of the enveloping layer and lack of autoneuralization in zebrafish embryonic explants. Dev Dyn. 2005 Jan; 232(1):85-97.
          View in: PubMed
        15. Nakamura M, Runko AP, Sagerström CG. A novel subfamily of zinc finger genes involved in embryonic development. J Cell Biochem. 2004 Nov 15; 93(5):887-95.
          View in: PubMed
        16. Choe SK, Sagerström CG. Paralog group 1 hox genes regulate rhombomere 5/6 expression of vhnf1, a repressor of rostral hindbrain fates, in a meis-dependent manner. Dev Biol. 2004 Jul 15; 271(2):350-61.
          View in: PubMed
        17. Sagerström CG. PbX marks the spot. Dev Cell. 2004 Jun; 6(6):737-8.
          View in: PubMed
        18. Roy NM, Sagerström CG. An early Fgf signal required for gene expression in the zebrafish hindbrain primordium. Brain Res Dev Brain Res. 2004 Jan 31; 148(1):27-42.
          View in: PubMed
        19. Runko AP, Sagerström CG. Isolation of nlz2 and characterization of essential domains in Nlz family proteins. J Biol Chem. 2004 Mar 19; 279(12):11917-25.
          View in: PubMed
        20. Runko AP, Sagerström CG. Nlz belongs to a family of zinc-finger-containing repressors and controls segmental gene expression in the zebrafish hindbrain. Dev Biol. 2003 Oct 15; 262(2):254-67.
          View in: PubMed
        21. Lane ME, Runko AP, Roy NM, Sagerström CG. Dynamic expression and regulation by Fgf8 and Pou2 of the zebrafish LIM-only gene, lmo4. Gene Expr Patterns. 2002 Dec; 2(3-4):207-11.
          View in: PubMed
        22. Lane ME, Runko AP, Roy NM, Sagerström CG. Dynamic expression and regulation by Fgf8 and Pou2 of the zebrafish LIM-only gene, lmo4. Mech Dev. 2002 Dec; 119 Suppl 1:S185-9.
          View in: PubMed
        23. Etheridge L, Diiorio P, Sagerström CG. A zebrafish unc-45-related gene expressed during muscle development. Dev Dyn. 2002 Aug; 224(4):457-60.
          View in: PubMed
        24. Choe SK, Vlachakis N, Sagerström CG. Meis family proteins are required for hindbrain development in the zebrafish. Development. 2002 Feb; 129(3):585-95.
          View in: PubMed
        25. Sagerström CG, Kao BA, Lane ME, Sive H. Isolation and characterization of posteriorly restricted genes in the zebrafish gastrula. Dev Dyn. 2001 Apr; 220(4):402-8.
          View in: PubMed
        26. Vlachakis N, Choe SK, Sagerström CG. Meis3 synergizes with Pbx4 and Hoxb1b in promoting hindbrain fates in the zebrafish. Development. 2001 Apr; 128(8):1299-312.
          View in: PubMed
        27. Vlachakis N, Ellstrom DR, Sagerström CG. A novel pbx family member expressed during early zebrafish embryogenesis forms trimeric complexes with Meis3 and Hoxb1b. Dev Dyn. 2000 Jan; 217(1):109-19.
          View in: PubMed
        28. Grinblat Y, Lane ME, Sagerström C, Sive H. Analysis of zebrafish development using explant culture assays. Methods Cell Biol. 1999; 59:127-56.
          View in: PubMed
        29. Sagerström CG. Slippery slopes: Understanding gradients and asymmetries in development. Trends Cell Biol. 1997 Nov; 7(11):463-5.
          View in: PubMed
        30. Sagerström CG, Sun BI, Sive HL. Subtractive cloning: past, present, and future. Annu Rev Biochem. 1997; 66:751-83.
          View in: PubMed
        31. Sagerström CG, Grinbalt Y, Sive H. Anteroposterior patterning in the zebrafish, Danio rerio: an explant assay reveals inductive and suppressive cell interactions. Development. 1996 Jun; 122(6):1873-83.
          View in: PubMed
        32. Sagerström CG, Kerr EM, Allison JP, Davis MM. Activation and differentiation requirements of primary T cells in vitro. Proc Natl Acad Sci U S A. 1993 Oct 1; 90(19):8987-91.
          View in: PubMed
        33. Devaux B, Bjorkman PJ, Stevenson C, Greif W, Elliott JF, Sagerström C, Clayberger C, Krensky AM, Davis MM. Generation of monoclonal antibodies against soluble human T cell receptor polypeptides. Eur J Immunol. 1991 Sep; 21(9):2111-9.
          View in: PubMed
        34. Lin AY, Devaux B, Green A, Sagerström C, Elliott JF, Davis MM. Expression of T cell antigen receptor heterodimers in a lipid-linked form. Science. 1990 Aug 10; 249(4969):677-9.
          View in: PubMed
        35. Davis MM, Berg LJ, Lin AY, Fazekas de St Groth B, Devaux B, Sagerstrom CG, Bjorkman PJ, Elliott JF. TCR recognition and selection in vivo. Cold Spring Harb Symp Quant Biol. 1989; 54 Pt 1:119-28.
          View in: PubMed
        For assistance with using Profiles, please refer to the online tutorials or contact UMMS Help Desk or call 508-856-8643.
        Charles's Networks
        Click the "See All" links for more information and interactive visualizations!
        Concepts
        _
        Co-Authors
        _
        Similar People
        _
        Same Department
        Physical Neighbors
        _

        This is an official Page/Publication of the University of Massachusetts Worcester Campus
        Office of the Vice Provost for Research, 55 Lake Ave North, Worcester, Massachusetts 01655
        Questions or Comments? Email: publicaffairs@umassmed.edu Phone: 508-856-1572