Postdoctoral Position Available

Jeffrey Nickerson, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cell Biology

Nuclear Architecture and Gene Expression

Nucleic acid metabolism is architecturally organized in the eukaryotic nucleus. Nucleic acids themselves- as well as their metabolism in transcription, RNA processing, and RNA export- are structurally constrained to dynamic nuclear domains. Our larger goal is to understand the mechanisms that accomplish the self-assembly of these domains and achieve the spatial organization of gene expression. Our approach is an interdisciplinary one, combining biochemistry and molecular biology with confocal and electron microscopy.

One ongoing project studies the role of the nuclear matrix protein, SRm160, in RNA splicing and export. SRm160 is recruited to pre-mRNA during spliceosome formation, participates in splicing, and then is retained as part of an Exon Junction Complex (EJC) of proteins bound to the fully processed mRNA. This EJC facilitates the efficient export of mRNA from the nucleus to the cytoplasm. The EJC restructures at the periphery of the nucleus and SRm160 is retained in the nucleus and recycled.

One of our current approaches is to track the movement of EJC complexes and components in the nuclei of live cells by time-lapse confocal microscopy and fluorescence recovery after photobleaching (FRAP). New FRAP techniques we have developed have shown that the intranuclear mobility of the EJC components SRm160 and RNPS1 is ATP dependent, suggesting that their assembly into complexes and movement are regulated. Electron microscopy studies of the SRm160 distribution have shown tracks of the protein between sites of RNA splicing and the nuclear lamina. Our working model, combining these observations is that SRm160-containing complexes may move toward the cytoplasm by a docking-release mechanism regulated by ATP. Stringing binding sites along a track would tend to constrain diffusion to preferred paths within the nucleus.

Other ongoing studies projects study additional protein components of the EJC, study the SRm160-interacting splicing factor SRm300, and measure the binding and mobility of mRNA itself in the nucleus. One collaborative project studies the changes in nuclear and chromatin structure that accompany and facilitate the tissue formation of human breast epithelial cells. We continue to develop new techniques for FRAP experiments and for the analysis of FRAP results.

Figure

Figure: Resinless section of a CaSki cell nuclear matrix. Soluble proteins and chromatin have been removed from this nucleus, uncovering the nuclear matrix which consists of two parts. The nuclear lamina is the outer shell of the matrix which lies just under the nuclear envelope and is primarily composed to the lamin proteins A, B, and C. Connected to the lamina and extending throughout the nuclear volume is the internal nuclear matrix, an intricate structure built on a scaffolding of 10 nm filaments whose molecular composition remains unknown. The largest masses remaining in the interior are remnants of nucleoli.

Recent Publications

Nickerson, J. A.  2009.  The biochemistry of RNA metabolism studied in situ.  RNA Biol. 6:25-30.

Imbalzano K. M., I. Tatarkova, A. N. Imbalzano, and J. A. Nickerson.  2009.  Increasingly transformed MCF-10A cells have a progressively tumor-like phenotype in three-dimensional basement membrane culture.  Cancer Cell Int.9:7.

Kota, K.P., S.R. Wagner, E. Huerta, J.M. Underwood, and J.A. Nickerson. 2008. Binding of ATP to UAP56 is necessary for mRNA export. J Cell Sci. 121:1526-1537.

Pockwinse, S.M., S.K. Zaidi, R.F. Medina, R. Bakshi, K.P. Kota, S.A. Ali, D.W. Young, J.A. Nickerson, A. Javed, M. Montecino, A.J. van Wijnen, J.B. Lian, J.L. Stein, and G.S. Stein. 2008. In situ nuclear organization of regulatory machinery. Methods Mol Biol. 455:239-259.

Young, D.W., M.Q. Hassan, J. Pratap, M. Galindo, S.K. Zaidi, S.H. Lee, X. Yang, R. Xie, A. Javed, J.M. Underwood, P. Furcinitti, A.N. Imbalzano, S. Penman, J.A. Nickerson, M.A. Montecino, J.B. Lian, J.L. Stein, A.J. van Wijnen, and G.S. Stein.  2007.  Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature 445: 442-446.
    
Vradii, D., S. Wagner, D.N. Doan, J.A. Nickerson, M. Montecino, J.B. Lian, J.L. Stein, A.J. van Wijnen, A.N. Imbalzano, and G.S. Stein.  2006. Brg1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for myeloid differentiation to granulocytes. J Cell Physiol  206: 112-118.

Underwood, J. M., K. M. Imbalzano, V. M. Weaver, A. H. Fischer, A. N. Imbalzano, and J. A. Nickerson. 2006. The Ultrastructure of MCF-10A Acini.  J Cell Physiol  8: 141-148.

Lele, T., Wagner, S. W., Nickerson, J. A., and D. E. Ingber. 2006. Methods for Measuring Rates of  Protein  Binding to Insoluble Scaffolds in Living Cells: Histone H1-chromatin interactions.  J Cell Biochem 99: 1334-1342.
    
Pockwinse, S.M., A. Rajgopal, D.W. Young, K.A. Mujeeb, J. Nickerson, A. Javed, S. Redick, J.B. Lian, A.J. van Wijnen, J.L. Stein, G.S. Stein, and S.J. Doxsey.  2006.  Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2. J Cell Physiol 206: 354-62.
    
Vradii, D., Wagner, S., Doan, D. N., Nickerson, J. A., Montecino, M., Lian, J. B., Stein, J. L., van Wijnen, A. J., Imbalzano, A. N. and Stein, G. S.  2006.  Brg1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for myeloid differentiation to granulocytes. J Cell Physiol 206:112-118.
    
McCracken, S., Longman, D., Marcon, E., Moens, P., Downey, M., Nickerson, J. A., Jessberger, R., Wilde, A., Caceres, J. F., Emili, A., and Blencowe, B. J.  2005.  Proteomic analysis of SRm160-containing complexes reveals a conserved association with cohesin. J Biol Chem. 280:42227-42236.
    
Heisterkamp, A., I. Z. Maxwell, E. Mazur, J. M. Underwood, J. A. Nickerson, S. Kumar, and D. E. Ingber  2005. Pulse energy dependence of subcellular dissection by femtosecond laser pulses. Opt Express 13, 3690-3696.
    
Liu, F., S. Wagner, R. B. Campbell, J. A. Nickerson, C. A. Schiffer, and A. H. Ross.  2005. PTEN enters the nucleus by diffusion. J Cell Biochem 96, 221-234.

Zink, D., A.H. Fischer, and J. A. Nickerson. 2004. Nuclear structure in cancer cells. Nat Rev Cancer. 4:677-687.

D. A. Hill, S. Chiosea, K. Roy, A. H. Fischer, D. D. Boyd, J. A. Nickerson, and A. N. Imbalzano^. 2004.  Inducible changes in cell and nuclear size due to expression of dominant negative SWI/SNF chromatin remodeling enzymes. J. Cell Science (in press).

Lele, T., P. Oh, J. A. Nickerson, D. E. Ingber. 2004. An improved mathematical model for determination of molecular kinetics in living cells with FRAP. Mechanics & Chemistry of Biosystems 1:181-190.

Wagner, S., S. Chiosea, M. Ivshina, and J. A. Nickerson. 2004. In vitro FRAP reveals the ATP-dependent nuclear mobilization of the exon junction complex protein SRm160.   J Cell Biology 164:843-850..

Wagner, S., S. Chiosea, and J. A. Nickerson. 2003.  The Spatial Targeting and Nuclear Matrix Binding Domains of SRm160.  Proc. Natl. Acad. Sci. U.S.A. 100: 3269-3274.

Herbert, A., S. Wagner, and J. A. Nickerson. 2002.  Induction of Protein Translation by ADAR1 Within Living Cell Nuclei is not dependent of RNA Editing.  Molecular Cell 10: 1235-1246.

Barseguian, K., B. Lutterbach, S. W. Hiebert, J. Nickerson, J. B. Lian, J. L. Stein, A. J. VanWijnen, and G. S. Stein. 2002. Multiple subnuclear targeting signals of the leukemia related AML1/ETO and ETO repressor proteins. Proc. Natl. Acad. Sci. U.S.A.  99: 15434-15439.

Nickerson, J. A.  2001.  Experimental Observations of a Nuclear Matrix.  J. Cell Sci., 114: 463-474.

McGarvey, T., E. Rosonina, S. McCracken, Q. Li, R. Arnaout, J. A. Nickerson, D. Arey, J. Greenblatt, G. Grosveld,  and B. J. Blencowe, B. J.  2000.  The acutemyeloid leukemia-associated protein DEK forms a splicing-dependent interaction with mRNP.  Journal of Cell Biology 150:309-320.

Blencowe, B. J., G. Bauren, A. G. Eldridge, R. Issner, J. A. Nickerson, E. Rosonina, and P. A. Sharp.  2000.  The SRm160/300 splicing co-activator subunits.  RNA 6: 111-120.

Mancini, M., and J. Nickerson. 1999  Special-interest subgroups at the ASCB: Nuclear dynamics at mitosis.  Trends Cell Biol., 120.                                  

Wan, K. M., J. A. Nickerson, G. Krockmalnic, and S. Penman.  1999.  The Nuclear Matrix Prepared by Amine Modification.  Proc. Natl. Acad. Sci. U.S.A. 96: 933-938.

Lelievre, S.A., V.M. Weaver, J.A. Nickerson, C.A. Larabell, A. Bhaumik, O.W. Petersen, and M.J. Bissell. 1998. Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. Proc. Natl. Acad. Sci. U. S. A. 95: 14711-14716.

Nickerson, J. A.  1998.  Nuclear Dreams: Malignant Alterations in Nuclear Architecture.  Journal of Cellular Biochemistry 70: 172-180.

Blencowe, B. J., R. Issner, J. A. Nickerson, and P. A. Sharp.  1998.  A Coactivator of pre-mRNA Splicing.  Genes and Development 12: 996-1009.

Zeng, C., S. McNeil, S. Pockwinse, J. Nickerson, L. Shopland, J.B. Lawrence, S. Penman, S. Hiebert, J.B. Lian, A.J. van Wijnen, J.L. Stein, and G.S. Stein. 1998. Intranuclear targeting of AML/CBFalpha regulatory factors to nuclear matrix-associated transcriptional domains. Proc. Natl. Acad. Sci. U. S. A. 95:1585-1589.

Nickerson, J. A., G. Krockmalnic, K. M. Wan, and S. Penman.  1997.  The Nuclear Matrix Revealed by Eluting Chromatin from a Crosslinked Nucleus.  Proc. Natl. Acad. Sci. U. S. A. 94: 4446-4450.

Potential Rotation Projects

1. Determine the effects of SRm160 depletion on the rates of RNA splicing in human cells. Splicing rates will be measured with splicing reporter constructs after treatment of cells with antisense and RNAi oligonucleotides.
   
   
2. Create a stable cell lines expressing green fluorescent protein fused with SRm300. The movement of GFP-SRm300 in living cells will then be measured by time lapse fluorescence microscopy and by confocal microscopy after laser photobleaching.

Academic Background

Ph.D., 1985, Michigan State University

Office: S7-212 ,LAB /221
Phone: 508-856-2312
E-mail: Jeffrey.Nickerson@umassmed.edu
Keywords: Cell Biology, Cell Cycle, Gene Expression

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Postdoctoral Position Available POSTDOCTORAL POSITION – IMMEDIATE OPENING Molecular Mechanisms of Breast Tissue Differentiation and Oncogenesis A position is available immediately to examine the mechanisms controlling breast tissue differentiation, maintenance, and tumorigenesis, with an emphasis on gene regulatory pathways, and higher order chromatin and nuclear structure using an approach intergrating cell and molecular biology.  Good verbal and written English skills are required.  Send c.v. and contact information for 3 references to: Jeffrey A. Nickerson, Ph.D. or Anthony N. Imbalzano, Ph.D., Department of Cell Biology UMass  Medical  School 55 Lake Avenue North Worcester, MA  01655 Email: anthony.imbalzano@umassmed.edu or jeffrey.nickerson@umassmed.edu   POSTDOCTORAL POSITION A Postdoctoral Position is available immediately in the Department of Cell Biology to study nuclear proteins that participate in RNA processing and export. One of these proteins, SRm160, functions in splicing and then remains bound to the spliced mRNA in the Exon Junction Complex (EJC) that facilitates the export of the mRNA to the cytoplasm.  The Postdoctoral Associate would determine the role that SRm160 and its EJC partners play in mRNA export to the cytoplasm. (See: Wagner et al.  2004.  J Cell Biology 164:843-850)  The experimental approach will integrate molecular and microscopy techniques. Candidates with a strong background in cell biology, biochemistry, or molecular biology are especially desirable. The University of Massachusetts Medical School is located close to Boston.   The Department of Cell Biology has especially strong research programs in nuclear and chromatin structure, cytoskeletal function, and mitotic architecture. The Department supports good core facilities for confocal microscopy, electron microscopy, the development of transgenic mice, and molecular biology. Interested candidates should contact: Jeffrey A. Nickerson, Ph.D. Department of Cell Biology S7-214 University of Massachusetts Medical School 55 Lake Avenue North Worcester, MA 01655 (508) 856-2312 jeffrey.nickerson@umassmed.edu