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    Thomas G Fazzio PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-519
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

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

        Overview 
        Narrative

        Academic Information

        Thomas Fazzio received his B.S. degree from the University of Utah in 1997, where he studied the genetics of Vitamin B12 metabolism in Salmonella typhimurium, in the laboratory of John Roth. Tom received his Ph.D. from the University of Washington and Fred Hutchinson Cancer Research Center in 2004 for work on yeast chromatin regulation in the lab of Toshio Tsukiyama. Tom did postdoctoral work on chromatin regulation in stem cells at the University of California, San Francisco in the labs of Barbara Panning and J. Michael Bishop. This work was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and a Pathway to Independence Award from the NIH. Tom joined the Program in Gene Function and Expression at the University of Massachusetts Medical School in spring 2010.

        Chromatin Regulation in Stem Cells

        Thomas FazzioIn eukaryotes, relatively large amounts of DNA must be packed into microscopic nuclei within each cell. This is achieved via the formation of highly-organized, yet dynamic chromatin structure in cells. Chromatin affects nuclear processes like gene expression, DNA replication and recombination by several mechanisms, including inhibition of transcription factor binding and localization of genes to transcriptionally active or inactive regions of the nucleus.

        Stem cells – cells that are capable of generating any cell type of a tissue or organism – need to remain developmentally flexible in order to be able to self-renew (generate more stem cells) or differentiate into various somatic cell types. To maintain this flexibility, embryonic stem cells maintain a unique chromatin structure that is unusually dynamic and exhibits an atypical pattern of histone modifications at the regulatory sequences of some developmentally regulated genes. In spite of this, the functions of chromatin structure in regulation of stem cell fate remain largely unknown.

        We are interested in the mechanisms by which chromatin structure and chromatin regulatory proteins impact gene expression, self-renewal and differentiation in stem cells. To study these processes, we utilize an array of molecular, cellular, genetic, biochemical and systems level approaches.

        Chromatin Regulation and Embryonic Stem Cell Self-Renewal

        Chromatin structure in embryonic stem (ES) cells is distinct from differentiated cells. ES cells lack large domains of heterochromatin and have unusual patterns of histone modifications at the regulatory regions of some genes. In addition, the chromatin of ES cells is extremely dynamic, exhibiting rapid exchange of chromatin proteins on and off of DNA. However, the functions of this unusual chromatin structure in ES cell self-renewal and differentiation are mysterious.

        In an RNA-interference (RNAi) screen of most chromatin proteins in mouse, we recently identified a number of chromatin regulatory proteins necessary for ES cell proliferation or self-renewal. However, the targets of these proteins, along with their cellular functions in ES cell self-renewal, remain largely unknown. Currently, we are examining the functions of some of these chromatin regulators, their regulation, and how they fit into the known transcriptional network governing ES cell pluripotency.

        Functions and Regulation of the Tip60-p400 Chromatin Remodeling Complex

        One important chromatin regulator in ES cells is the Tip60-p400 complex. Tip60-p400 has both histone exchange and histone acetyltransferase (HAT) activities, and functions in gene regulation and DNA damage repair.

        We found that RNAi-mediated knockdown (KD) of any of the 17 subunits of the Tip60-p400 complex in ES cells inhibited self-renewal. However, the molecular functions of Tip60-p400 necessary for self-renewal remain unclear. Although the Tip60 HAT activity has been implicated in gene activation in somatic cells, the primary effect of Tip60 KD in ES cells was activation of genes induced during differentiation. The promoters of many of these genes are directly bound and acetylated by Tip60-p400, raising the question of how this complex might be repressing transcription (Figure 1). We are currently working to dissect the mechanisms by which Tip60-p400 regulates genes in ES cells, and how Tip60-p400 activity is regulated upon ES cell differentiation.

        Figure 1. Possible mechanisms for Tip60-p400-mediated repression.

        Figure 1. Possible mechanisms for Tip60-p400-mediated repression. (A) Acetylation-mediated activation of a repressor. Tip60, which also acetylates non-histone proteins, may activate a transcriptional repressor (TR) by acetylation, causing it to bind its target sequence and repress transcription. (B) Dual-modification repressor binding. Tip60-mediated histone acetylation, plus a second chromatin modification (or alternatively, a specific DNA sequence), might recruit a repressor specific for chromatin harboring both modifications. HMC: histone modifying complex. Adapted from Fazzio et al., Cell Cycle 7:21, 3302-3306.

        Chromatin Regulation and Cancer Stem Cells

        While embryonic stem cells, adult stem cells and cancer stem cells (cells within some tumors that can self-renew indefinitely and reconstitute the entire tumor on their own) have very different cellular properties, their chromatin structures share some common features. One example is the polycomb repressive complex 1 (PRC1) protein Bmi-1, which is required for self-renewal in a number of stem cell types. It is unclear whether there are many other chromatin regulators are similarly required for maintenance of developmental potency. We are addressing this question by testing whether chromatin regulators necessary for proliferation or self-renewal of ES cells are also essential in cancer stem cells. Our goals for these experiments are to learn more about the common features of chromatin structure in developmentally plastic cells, as well as identify potential new targets for drugs that target stem cells within tumors.



        Rotation Projects

        Rotation Projects

        Rotation projects are available on any of the main topics being studied in the lab. Our recent RNAi screen identifying chromatin regulators necessary for ES cell self-renewal has opened up several new potential projects aimed at identification of the important functions of these regulators in ES cells. Alternatively, projects focusing on the mechanisms of action and regulation of Tip60-p400 complex, or examining the functions of chromatin regulators in cancer stem cells are also possible, depending on the student’s interests. Rotation projects will usually involve some combination of mammalian cell culture, cell and molecular biology, biochemistry, and genomic approaches.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Please contact Dr. Fazzio for details.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Fazzio TG, Rando OJ. NURDs are required for diversity. EMBO J. 2012; 31(14):3036-7.
          View in: PubMed
        2. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS, Weng Z, Rando OJ, Fazzio TG. Mbd3/NURD Complex Regulates Expression of 5-Hydroxymethylcytosine Marked Genes in Embryonic Stem Cells. Cell. 2011 Dec 23; 147(7):1498-510.
          View in: PubMed
        3. Fazzio TG, Panning B. Control of embryonic stem cell identity by nucleosome remodeling enzymes. Curr Opin Genet Dev. 2010 Oct; 20(5):500-4.
          View in: PubMed
        4. Fazzio TG, Panning B. Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells. J Cell Biol. 2010 Feb 22; 188(4):491-503.
          View in: PubMed
        5. Fazzio TG, Huff JT, Panning B. Chromatin regulation Tip(60)s the balance in embryonic stem cell self-renewal. Cell Cycle. 2008 Nov 1; 7(21):3302-6.
          View in: PubMed
        6. Fazzio TG, Huff JT, Panning B. An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell. 2008 Jul 11; 134(1):162-74.
          View in: PubMed
        7. Nusinow DA, Hernández-Muñoz I, Fazzio TG, Shah GM, Kraus WL, Panning B. Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome. J Biol Chem. 2007 Apr 27; 282(17):12851-9.
          View in: PubMed
        8. Fazzio TG, Gelbart ME, Tsukiyama T. Two distinct mechanisms of chromatin interaction by the Isw2 chromatin remodeling complex in vivo. Mol Cell Biol. 2005 Nov; 25(21):9165-74.
          View in: PubMed
        9. Price-Carter M, Fazzio TG, Vallbona EI, Roth JR. Polyphosphate kinase protects Salmonella enterica from weak organic acid stress. J Bacteriol. 2005 May; 187(9):3088-99.
          View in: PubMed
        10. Vary JC, Fazzio TG, Tsukiyama T. Assembly of yeast chromatin using ISWI complexes. Methods Enzymol. 2004; 375:88-102.
          View in: PubMed
        11. Fazzio TG, Tsukiyama T. Chromatin remodeling in vivo: evidence for a nucleosome sliding mechanism. Mol Cell. 2003 Nov; 12(5):1333-40.
          View in: PubMed
        12. Carey JF, Schultz SJ, Sisson L, Fazzio TG, Champoux JJ. DNA relaxation by human topoisomerase I occurs in the closed clamp conformation of the protein. Proc Natl Acad Sci U S A. 2003 May 13; 100(10):5640-5.
          View in: PubMed
        13. Kooperberg C, Fazzio TG, Delrow JJ, Tsukiyama T. Improved background correction for spotted DNA microarrays. J Comput Biol. 2002; 9(1):55-66.
          View in: PubMed
        14. Fazzio TG, Kooperberg C, Goldmark JP, Neal C, Basom R, Delrow J, Tsukiyama T. Widespread collaboration of Isw2 and Sin3-Rpd3 chromatin remodeling complexes in transcriptional repression. Mol Cell Biol. 2001 Oct; 21(19):6450-60.
          View in: PubMed
        15. Goldmark JP, Fazzio TG, Estep PW, Church GM, Tsukiyama T. The Isw2 chromatin remodeling complex represses early meiotic genes upon recruitment by Ume6p. Cell. 2000 Oct 27; 103(3):423-33.
          View in: PubMed
        16. Fazzio TG, Roth JR. Evidence that the CysG protein catalyzes the first reaction specific to B12 synthesis in Salmonella typhimurium, insertion of cobalt. J Bacteriol. 1996 Dec; 178(23):6952-9.
          View in: PubMed
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