Postdoctoral Position Available

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Jeanne Lawrence, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Cell Biology
   Pediatrics

Genome Organization and the Functional Relationship of DNA/RNA with Nuclear Structure

Research interests of the lab bridge the basic cell and developmental biology of nuclear organization with human genetics, using skeletal muscle differentiation as one developmental model system. A major focus is the localization and functional organization of specific genes and their cognate mRNAs within the mammalian nucleus, as well as the potential compartmentalization of the nucleus with respect to components involved in RNA metabolism. Fundamental questions concerning both the higher-level organization of DNA and gene transcription within nuclei or chromosomes, as well as the transport and processing of nuclear RNA as it relates to nuclear structure, have been poorly explored. Recently, it has been shown that the nucleoplasm is compartmentalized: poly A RNA and splicing components are concentrated in discrete regions. These regions provide internal reference points with which to investigate the spatial arrangement of genes and RNAs within the nucleus, and results to date support a sequence-specific higher-level organization. Another current major focus of the lab is the mechanism of inactivation of the mammalian X-chromosome, and in particular the relationship of XIST RNA to X inactivation. This ongoing work provides evidence that XIST RNA may provide an important precedent for a long-lived nuclear poly A RNA involved in chromatin or nuclear structure and possibly gene regulation. Other projects involve the mapping and chromosome organization of cell growth related genes and their potential relationship to chromosomal aberrations prevalent in cancer or genetic disease. We are continuing to develop new biochemical fractionation and in situ hybridization approaches for investigating packaging of specific DNA sequences with respect to higher level chromatin loops and to examine gene packaging, with emphasis on specific regions of interest such as the trinucleotide repeats involved in Fragile X retardation.

Figure

Nuclear RNA from the human collagen gene (black) localizes within discrete domains greatly enriched in splicing components. Immunofluorescence (white) using antibodies to the spliceosome assembly factor, SC-35, is used to stain the domains, and RNA from the collagen gene (black) is detected by fluorescence in situ hybridization. Both the transcription and splicing of this RNA is associated with the domains.

Recent Publications

Hall., L.L., Byron, M., Butler, J., Becker, K., Nelson, A., Amit, M., Itskovitz-Eldor, J., Stein, J., Stein, G., Ware, C., and Lawrence, J.B., 2008. X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected. (J Cell Physiol. 2008 Mar 13; [Epub ahead of print])

Chow, J.C., Hall, L.L., Baldry, S.E., Thorogood, N.P., Lawrence, J.B., Brown, C.J., 2007.  Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible. PNAS,Jun12;104(24):10104-9.

Smith, K.P., Xing, Y., Johnson, C., Byron, M., and Lawrence, J. B., Defining early steps in mRNA export: Mutant mRNA in Myotonic Dystrophy Type I is blocked at entry into SC35 domains J Cell Biol. Vol. 178, No. 6, September 10, 2007.

Chow, J.C., Hall, L.L., Baldry, S.E., Thorogood, N.P., Lawrence, J.B., Brown, C.J. (2007).  Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible. PNAS, Jun 12;104(24):10104-9.

Pageau, G. J., Hall, L.L., Ganesan, S.G., Livingston, D.M., and Lawrence, J.B.  The Disappearing Barr Body in Breast and Ovarian Cancer.  Nat Rev Cancer, 2007 Aug;7(8):628-33.

Hutchinson, J.N., Ensminger, S.W., Clemson, C.M., Lynch, C.R., Lawrence, J.B., Chess, A., 2007.  A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains.  GMC Genetics, 2007 Feb 1;8:39. 

Pageau, G.J., Lawrence, J.B., BRCA1 foci in normal S-phase nuclei are linked to interphase centromeres and replication of pericentric heterochromatin.  J Cell Biol. 2006 Dec 4;175(5):693-701.

Pageau, G.J., Hall, L.L., Lawrence, J.B., 2006.  BRCA1 does not paint the inactive X to localize XIST RNA but may contribute to broad changes in cancer that impact XIST and Xi heterochromatin. J Cell Biochem., Dec. 4;100(4):835-850.

Hall, LL, Smith, K., and Lawrence, J.B. The Molecular Anatomy of a speckle, The Anatomical Record June 7, 2006.

Clemson, C.M., Hall, L.L., Byron, M., and Lawrence, J.B., 2006.  The X Chromosome Is Organized Into A Gene-Rich Outer Territory And An Internal Core Containing Silenced Non-Genic Sequences, PNAS  | May 16, 2006 | vol. 103 | no. 20 | 7688-7693.

McNeil, J., Smith, K.P., Hall, LL, and Lawrence, J.B., 2006.  Word Frequency Analysis Reveals Enrichment Of Dinucleotide Repeats On The Human X Chromosome And [GATA] n In The X Escape Region, Genome Research, Apr;16(4):477-84.

Hoffman, L.M, Hall, L., Batten, J.L., Young, H., Pardasani, D., Baetge E., Lawrence, J.B., Carpenter, M.K., 2005.  X-inactivation status varies in human embryonic stem cell line, Stem Cell Biology, Nov-Dec; 23 (10): 1468-78.

Smith, K.P., Byron, M., Clemson, C.M., and Lawrence, J.B. 2004.  Ubiquitinated proteins including uH2A on the human and mouse inactive X chromosome: enrichment in gene rich bands.  Chromosoma, 113: 324-335.

Tam, R., Smith, K.P., and Lawrence, J.B., 2004.  The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres. J. Cell Biol., Oct 25;167(2):269-79.

Smith, K.P., Byron, M., O’Connell, B., Tam, R., Schorl, C., Gueny, I., Hall, L., Agrawal, P. Sedivy, J. and Lawrence, J.B., 2004.  c-Myc Localization in the Nucleus: Evidence for Association with the PML Nuclear Body J Cell Biochem. Oct 22;93(6):1282-1296.

Moen, P.T., Johnson, C.V, Byron, M., Shopland, L.S, de la Serna, I., Imbalzano, A., and J.B. Lawrence, 2004.  Repositioning of muscle-specific genes to the periphery of SC-35 domains during skeletal myogenesis, Mol Biol Cell, 2004 Jan;15(1):197-206.

Kelly P. Smith and Jeanne B. Lawrence, Nuclear Compartmentalization (Splicing Factor   Domains, PML Nuclear Bodies, Cajal Bodies). Encyclopedia of Biological Chemistry 2004.

Hall, L.L., and Lawrence  , J.B., 2003.  The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade, (Requested Review, Seminars in Cell & Development Biology, 14 (2003).

Jennifer Chow, Lisa Hall, Christine Clemson, Jeanne B. Lawrence, Carolyn J. Brown, 2003. Characterization of Expression at the Human XIST Locus in Somatic, Embryonal Carcinoma and Transgenic Cell Lines, Genomics, 2003 Sept; 82 (3): 309-322.

Shopland, L.S., Johnson, C.V., Byron, M., and Lawrence, J.B., 2003.  Clustering of multiple specific genes and gene-rich R-band around SC-35 domains: evidence for local euchromatic neighborhoods. J. of Cell Biol., 2003 Sept; Vol. 162(6):981-990.

Lawrence, J.B., and Hager, G. editors, Current Opinion in Cell Biology, Issue on “Nucleus and Gene Expression: motion meets architecture”, Vol. 15 No 3, June 2003 Page 255-258.

Oh, S. W., Pope, R. K., Smith, K. P., Crowley, J. L., Nebl, T., Jeanne B. Lawrence, and Luna, E. J., 2003. Archvillin, a Muscle-specific Isoform of Supervillin, Is an Early-expressed Component of the Costameric Membrane Skeleton, J. of Cell Science, 2003 June 1; 116(Pt 11)2261-75.

Shopland, L.S., Johnson, C.V., and Lawrence, J.B., 2002.  Evidence that all SC-35 domains contain mRNAs and that transcripts can be structurally constrained within these domains,  J Struct Biol. 2002 Oct;140(1):131-9.

Hall, L. L., Clemson, C. M., Byron, M., Wydner, K., and  Lawrence, J.B., 2002.  Unbalanced   X;Autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin, Human Molecular Genetics  Vol. 11, No. 25 3157-3165.

Hall, L.L., Byron, B., Sakai, K., Carrel, L., Willard, H.F., Lawrence, J.B., 2002. AnEctopic Human XIST gene can induce chromosome inactivation in postdifferentiation Human HT-1080 cells. Proc Natl Acad Sci June 25;99(13):8677-82.

Chow, J., Hall, L.L., Lawrence, J.B. and Brown, C.J., 2002.  Ectopic XIST Transcripts in Human Somatic Cells Show Variable Expression and Localization.   Cytogenetics & Genome Research, 99:92-98.

Shopland, L.S., Byron, M., Stein, J.L., Lian, J.B., Stein, G.S., and Lawrence, J.B., 2001.  Replication-dependent histone gene expression is related to Cajal body (CB) association but does not require sustained CB contact, Molecular Biology of the Cell, 12, 565-576.

Larsen, M., Ressler, S. J., Gerdes, M. J., Lu, B., Byron, M., Lawrence, J.B., and Rowley, D.R., 2000. The WFDCI gene encoding ps20 localizes to 16q24, a region of LOH in multiple cancers, Mammalian Genome, Sep;11(9):767-73.

Smith, K.P. and Lawrence, J.B., 2000.  Interactions of U2 Gene Loci and their nuclear transcripts with cajal (coiled) bodies: Evidence for pre-U2 within cajal bodies, Molecular Biology of the Cell, 11:2987-2998.

Johnson, C.V., Primorac, D., McKinstry, M., McNeil, J., Rowe, D. and Lawrence, J.B., 2000.  Tracking COL1A1 RNA in Osteogenesis Imperfecta: Splice-defective Transcripts Initiate Transport from the Gene but Are Retained within the SC35 Domain.  J. of Cell Biol., 150(3):417-431.

Shopland, L.S. and Lawrence, J.B., 2000.  Seeking Common Ground in Nuclear Complexity, J. Cell Biol. 150(1):F1-F4.

Primorac, D., Johnson, C.V., Lawrence, J.B., McKinstry, M.B., Stover, M.L., Schanfield, M.S., Anoelinoviae S., Tadiae, T., Rowe, D., 1999, Premature termination codon in the aggrecan gene of nanomelia and its influence on mRNA transport and stability, Croatian Med.J. 40(4):528-532.

Smith, K.P., Moen, P.T., Wydner, K.L., Coleman, J.R., and Lawrence, J.B., (1999) Processing of endogenous pre-mRNAs in association with SC-35 domains is gene specific. J. Cell Biol., 144, No.4, 617-629.

Clemson, C.M., Chow, J.C., Brown, C.J., and Lawrence, J.B. (1998) Stabilization and localization of Xist RNA are controlled by separate mechanisms and are not sufficient for X inactivation. J. Cell Biol., 142, No.1, 13-23.

Clemson, C.M., McNeil, J.A., Willard, H.F., and Lawrence, J.B. (1996) XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear/chromosome structure. J. Cell Biol., 132, No.3, 259-275.

Xing, Y., Johnson, C.V., Moen, P.T., McNeil, J.A., and Lawrence, J.B. (1995) Nonrandom gene organization: Structural arrangements of specific pre-mRNA transcription and splicing with SC-35 domains. J. Cell Biol., 131, No.6, Part 2, 1635-1647.

Moen, P.T., Smith, K.P., and Lawrence, J.B. (1995) Compartmentalization of specific pre-mRNA metabolism: an emerging view. Hum. Mol. Gen., Vol.4, Review 1779-1789.

Gerdes, M., Carter, K.C., Moen, P., and Lawrence, J.B. (1994) Dynamic changes in the higher-level chromatin organization of specific sequences revealed by in situ hybridization to nuclear halos. J. Cell Biol., 126: 289-304.

Xing, Y., Johnson, C., Dobner, P., and Lawrence, J.B. (1993) Higher-level organization of individual gene transcription and RNA splicing. Science, 259: 1326-1330.

Carter, K., Bowman, D., Carrington, C., Fogarty, K., McNeil, J., Fay, F., and Lawrence, J.B. (1993) A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus. Science, 259: 1330-1335.

Potential Rotation Projects

1. Very recently we have discovered evidence for a novel intranuclear body marked by an oncogenic protein mutated in many cancers. A high priority will now be to examine the relationship of this novel structure to growth control in normal and cancer cells, and its dynamic interactions with other know nuclear bodies and regulation of specific genes. Another project on nuclear compartments investigates the impact of triplet repeat mutations on expression, processing and transport of specific RNAs in human genetic diseases, such as myotonic dystrophy.



2. Recent studies indicate that there is sequence specificity in the relationship of XIST RNA to the chromosome. The role of XIST RNA in X-inactivation is being examined using transgenes in ES cells, and the sequence specificity is being approached using bioinformatic analysis of genomic sequence.

Academic Background

Ph.D., 1982, Brown University

More information

• Lawrence Lab Web page

Office: S7-137
Phone: 508-856-6015
E-mail: Jeanne.Lawrence@umassmed.edu
Keywords: Stem Cell Biology, Chromosome Structure & Dynamics, Cancer Biology, Nuclear Architecture, Medical Genetics

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Postdoctoral Position Available Post-Doctoral Positions Available Post-doctoral positions are available in research involving the role of nuclear non-coding RNAs in epigenetic modifications to chromatin in human embryonic stem cells, as well as gene therapeutic use of non-coding RNA. Contact Jeanne Lawrence by e-mail or at 508-856-6015.