CELL BIOLOGY Home Faculty Department Directory Seminars EducationNews Links
Primary Faculty  
Katherine Wilson, Ph.D.
Professor
Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe St., G10 WBSB
Baltimore, MD 21205
Telephone: 410-955-1801 (Office)
410-614-2654 (Lab)
Fax: 410-955-4129
Email: klwilson@jhmi.edu    
Affiliations: BCMB Graduate Program


 

 

 

 

 

 

 

Research Topic:  Nuclear envelope and Nuckleoskeleton

Within each cell is a NUCLEUS, the 'mothership' of the human genome and still the least-understood part of the cell. Chromosomes are enclosed by the nuclear envelope (NE) and communicate with the cytoplasm through Nuclear Pore Complexes (NPCs). The NE has two membranes separated by an aqueous ‘lumenal’ space. The inner and outer nuclear membranes are organized by at least two major families of integral membrane proteins that form a variety of LINC (links the nucleoskeleton and cytoskeleton) complexes and other NE ‘adhesions’. These meta-structures (NPCs, LINC complexes and other NE adhesions) are anchored to networks of nuclear intermediate filaments (nuclear ‘lamina’ networks) formed by lamin proteins. The NE, lamina and many other nucleoskeletal proteins somehow create and maintain the special three-dimensional environment in which chromosomes are properly organized, expressed, protected and replicated.

 
The inner nuclear membrane, facing the chromosomes, is home to over 100 unique integral membrane proteins, most of which are uncharacterized. Exceptions include the ‘LEM-domain’ (LAP2, Emerin, MAN1) family of NE and nucleoskeletal proteins, encoded by seven human genes. All LEM-domain proteins share a ~40-residue folded domain that confers direct binding to an essential chromatin-binding epigenetic regulator named Barrier to Autointegration Factor (BAF). All characterized LEM-domain proteins also bind directly to A- and/or B-type lamins, and are collectively required to efficiently segregate chromosomes and rebuild nuclear structure after mitosis. Mutations in these proteins are known to cause many human diseases, including muscular dystrophy, heart disease and ‘accelerated aging’ (progeria).
We focus on understanding the LEM-domain protein emerin, its partners BAF and lamins, and their links to human disease. Loss of emerin typically causes X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD). Emerin protein is expressed throughout the body, but EDMD affects only three tissues, with contractures of major tendons, slowly progressive muscle wasting, and ventricular conduction defects that can cause sudden cardiac arrest. EDMD can also be caused by mutations in at least five other genes including LMNA (encoding A-type lamins, required to anchor emerin at the nuclear inner membrane), SYNE1 and SYNE2 (respectively encoding nesprin-1 and nesprin-2 protein isoforms found in LINC complexes), TMEM43 (encoding LUMA, an inner membrane protein that associates with emerin), and FHL1 (a muscle-relevant transcription factor, not yet tested for potential binding to emerin). The remarkable fact that five EDMD-linked genes encode proteins that all mutually interact, suggests that EDMD disease might arise when the assembly or function of this proposed EDMD-relevant NE adhesion/signaling complex is perturbed.

EDMD Awareness: We are preparing an “EDMD Awareness” page on Facebook (~Dec. 2011). This site will allow people with EDMD to find each other, discuss their experiences and build a community that can help educate families and doctors about EDMD. In addition, this site will summarize scientific progress in understanding EDMD, and provide useful links.

Selected Publications

Simon DN and Wilson KL (2011; online Oct 5) The nucleoskeleton as a genome-associated dynamic network of networks. Nature Reviews Mol Cell Biol
Abstract. In the cytosol, actin polymers, intermediate filaments and microtubules can anchor to cell surface adhesions and interlink to form intricate networks. This cytoskeleton is anchored to the nucleus through LINC (links the nucleoskeleton and cytoskeleton) complexes that span the nuclear envelope and in turn anchor to networks of filaments in the nucleus. The metazoan nucleoskeleton includes nuclear pore-linked filaments, A‑type and B‑type lamin intermediate filaments, nuclear mitotic apparatus (NuMA) networks, spectrins, titin, ‘unconventional’ polymers of actin and at least ten different myosin and kinesin motors. These elements constitute a poorly understood ‘network of networks’ that dynamically reorganizes during mitosis and is responsible for genome organization and integrity.

Wilson KL and Dawson SC (2011) Functional evolution of nuclear structure. J. Cell Biology (in press)
Abstract. The evolution of the nucleus, the defining feature of eukaryotic cells, was long shrouded in speculation and mystery. There is now strong evidence that nuclear pore complexes (NPCs) and nuclear membranes co-evolved with the endomembrane system, and that the last eukaryotic common ancestor (LECA) had fully functional NPCs. Recent studies have identified many components of the nuclear envelope in living Opisthokonts, the eukaryotic supergroup that includes fungi and metazoan animals. These components include diverse chromatin-binding membrane proteins, and membrane proteins with adhesive lumenal domains that may have contributed to the evolution of nuclear membrane architecture. Further discoveries about the nucleoskeleton suggest that the evolution of nuclear structure was tightly coupled to genome partitioning during mitosis.

Montes de Oca RM, Andreassen PR and Wilson KL (2011) Barrier-to-Autointegration Factor influences specific histone modifications. Nucleus (in press)
 Abstract. Defects in the nuclear envelope or nuclear ‘lamina’ networks cause disease and can perturb histone posttranslational (epigenetic) regulation. Barrier-to-Autointegration Factor (BAF) is an essential but enigmatic lamina component that binds lamins, LEM-domain proteins, DNA and histone H3 directly. We report BAF copurified with nuclease-digested mononucleo-somes and associated with modified histones in vivo. BAF overexpression significantly reduced global histone H3 acetylation by 18%. In cells that stably overexpressed BAF three-fold, silencing mark H3-K27-Me1/3 and active marks H4-K16-Ac and H4-Ac5 decreased significantly. Significant increases were also seen for silencing mark H3-K9-Me3, active marks H3-K4-Me2, H3-K9/K14-Ac and H4-K5-Ac, and a mark (H3-K79-Me2) associated with both active and silent chromatin. Other increases (H3-S10-P, H3-S28-P and silencing mark H3-K9-Me2) did not reach statistical significance. BAF overexpression also significantly influenced cell cycle distribution. BAF associated in vivo with SET/I2PP2A (protein phosphatase 2A inhibitor; blocks H3 dephosphorylation) and G9a (H3-K9 methyltransferase), but showed no detectable association with HDAC1 or HATs. These findings reveal BAF as a novel epigenetic regulator, and are discussed in relation to BAF deficiency phenotypes, which include a hereditary progeria syndrome and loss of pluripotency in embryonic stem cells.

Simon DN, Zastrow MS and Wilson KL (2010) Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail. Nucleus 1:264-272.

Wilson KL (2010) Nuclear envelope and lamin B2 function in the central nervous system. Proc Natl Acad Sci USA 107:6121-6122.

Wilson KL and Berk JM (2010) The nuclear envelope at a glance. J Cell Science 123:1973-8.

Zhong Z, Chang SA, Kalinowski A, Wilson KL and Dahl KN (2010) Stabilization of the spectrin-like domains of nesprin-1a by the evolutionarily conserved “adaptive” domain. Cell Mol Bioeng 3:139-150.

Zhong Z, Wilson KL and Dahl KN (2010) Beyond lamins: other structural components of the nucleoskeleton. Methods Cell Biology 98:97-119.

Montes de Oca R, Shoemaker CJ, Gucek M, Cole RN and Wilson KL (2009) Barrier to Autointegration Factor proteome reveals chromatin-regulatory partners. PLoS One e7050.

Tifft KE, Bradbury KA and Wilson KL (2009) Tyrosine phosphorylation of nuclear membrane protein emerin by Src, Abl and other kinases. J Cell Science 122:3780-3790.

Wilson KL and Foisner R (2009) Lamin-binding proteins. Cold Spring Harb Perspect Biol 2:a000554.

Holaska JM and Wilson KL (2007) An emerin ‘proteome’: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechanosensing and nuclear architecture. Biochemistry 46, 8897-908.

Margalit A, Neufeld E, Feinstein N, Wilson KL, Podbilewicz B and Gruenbaum Y (2007) Barrier to autointegration factor (BAF) blocks premature cell fusion and maintains adult muscle integrity in C. elegans. J Cell Biology 178:661-673.

Zastrow MS, Flaherty DB, Benian GM and Wilson KL (2006) Nuclear titin interacts with A- and B-type lamins in vitro and in vivo. J. Cell Science 119, 239-249.

Montes de Oca R, Lee KK and Wilson KL (2006) Binding of barrier-to-autointegration factor (BAF) to histone H3 and selected linker histones including H1.1. J. Biol. Chemistry 280, 42252-62.

Tifft K, Segura-Totten M, Lee KK and Wilson KL (2006) Barrier-to-autointegration factor- (BAF-) Like, a proposed regulator of BAF. Exp. Cell Res. 312, 478-487.

Bengtsson L and Wilson KL (2006) Barrier-to-autointegration factor phosphorylation on Ser-4 regulates emerin binding to lamin A in vitro and emerin localization in vivo. Mol. Biol. Cell 17, 1154-1163.  

Wilson KL (2006) Integrity matters: linking nuclear architecture to lifespan.Proc Natl Acad Sci USA 102, 18767-8.

Dahl KN, Scaffidi P, Islam MF, Yodh AG, Wilson KL and Misteli T. (2006) Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford Progeria Syndrome. Proc Natl Acad Sci USA 103, 10271-10276.

Tzur YB, Wilson KL and Gruenbaum Y (2006) SUN-domain proteins: "Velcro" that links the nucleoskeleton to the cytoskeleton. Nature Rev Mol. Cell Biol. 7, 782-788. epub PMID: 16926857.

Holaska JM and Wilson KL (2006) Multiple roles for emerin: Implications for Emery-Dreifuss muscular dystrophy. Anat. Rec A Discov Mol Cell Evol Biol. 288, 676-680.

Holaska JM, Rais-Bahrami S and Wilson KL (2006) Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes. Human Mol. Genet. 15, 3459-3472.

Margalit A, Segura-Totten M, Gruenbaum Y and Wilson KL (2005) Barrier-to-autointegration factor is required to stably segregate and enclose chromosomes within the nuclear envelope and assemble the nuclear lamina. Proc. Natl. Acad Sci USA 102, 3290-3295.

Wilson KL, Holaska JM, Montes de Oca RM, Tifft K, Zastrow M, Segura-Totten M, Mansharamani M, Bengtsson L (2005) Nuclear membrane protein emerin: roles in gene regulation, actin dynamics and human disease. Novartis Found Symp. 264, 51-58; discussion 58-62, 227-230.

Mansharamani M and Wilson KL (2005) Nuclear membrane protein MAN1: direct binding to emerin in vitro and two modes of binding to BAF. J. Biol. Chem. 280, 13863-70.

Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK and Wilson KL (2005) The nuclear lamina comes of age. Nature Reviews Molecular Cell Biology 6, 21-31.

Lee KK and Wilson KL (2004) All in the family: evidence for four new LEM-domain proteins Lem2 (NET-25), Lem3, Lem4 and Lem5 in the human genome. Symp Soc Exp Biol 56, 329-339.

Vlcek S, Foisner R and Wilson KL (2004) Lco1 is a novel widely-expressed lamin-binding protein in the nuclear interior. Exp. Cell Res. 298, 499-511.

Dahl KN, Kahn SM, Wilson KL and Discher DE (2004) The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J. Cell Science 117, 4779-4786.

Holaska, J.M., Kowalski, A.K., Wilson, K.L. (2004) Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLOS Biology 2(9):E231.

Haraguchi, T., Holaska, J.M., Yamame, M., Koujin, T., Wilson, K.L. and Hiraoka, Y. (2004) Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy. Eur J Biochem 271:1035-45.

Segura-Totten, M. and Wilson, K.L. (2004) BAF: roles in chromatin, nuclear structure and retrovirus integration. Trends Cell Biol 14:261-266.

Kiseleva, E., Drummond, S.P., Goldberg, M.W., Rutherford, S.A., Allen, T.D. and Wilson, K.L. (2004) Actin- and protein-4.1-containing filaments link nuclear pore complexes to subnuclear organelles in Xenopus oocyte nuclei. J Cell Sci 117:2481-90.

Shimi, T., Koujin, T., Segura-Totten, M., Wilson, K.L., Haraguchi, T., Hiraoka, Y. (2004) Dynamic interaction between BAF and emerin revealed by FRAP, FLIP, and FRET analyses in living HeLa cells. J Struct Biol 147:31-41.

Fridkin, A., Mills, E., Margalit, A., Neufeld, E., Lee, K.K., Feinstein, N., Cohen, M., Wilson, K.L., Gruenbaum, Y. (2004) Matefin, a Caenorhabditis elegans germ line-specific SUN-domain nuclear membrane protein, is essential for early embryonic and germ cell development. Proc Natl Acad Sci USA. 101:6987-92.

Bengtsson, L. and Wilson, K.L. (2004) Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr Opin Cell Biol 16:73-79.

Zastrow, M.S., Vlcek, S. and Wilson, K.L. (2004) Proteins that bind A-type lamins: integrating isolated clues. J Cell Sci 117:979-87.

Mansharamani, M., Graham, D.R., Monie, D., Lee, K.K., Hildreth, J.E., Siliciano, R.F., Wilson, K.L. (2003) Barrier-to-autointegration factor BAF binds p55 Gag and matrix and is a host component of human immunodeficiency virus type 1 virions. J Virol 77:13084-92.

Cohen, M., Feinstein, N., Wilson, K.L. and Gruenbaum Y. (2003) Nuclear pore protein gp210 is essential for viability in HeLa cells and Caenorhabditis elegans. Mol Biol Cell 14:4230-7.

Wilkinson, F.L., Holaska, J.M., Zhang, Z., Sharma, A., Manilal, S., Holt, I., Stamm, S., Wilson, K.L. and Morris, G.E. (2003) Emerin interacts in vitro with the splicing-associated factor, YT521-B. Eur J Biochem 270:2459-66.

Holaska, J.M., Lee, K.K., Kowalski, A.K. and Wilson, K.L. (2003) Transcriptional repressor germ cell-less (GCL) and barrier-to-autointegration factor (BAF) compete for binding to emerin. J Biological Chemistry 278: 6969-6975.

Liu, J., Lee, K.K., Segura-Totten, M., Neufeld, E., Wilson, K.L. and Gruenbaum, Y. (2003) MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. Proc Natl Acad Sci 100: 4598-603

Wolfner, M.F. and Wilson, K.L. (2001) The nuclear envelope: emerging roles in development and disease. Cell Molec Life Sci 58: 1737-1740.

Wilson, K.L. (2000) The nuclear envelope, muscular dystrophy, and gene expression. Trends Cell Biology 10: 125-129.

Lee, K.K., Gruenbaum, Y., Spann, P., Liu, J. and Wilson, K.L. (2000) C. elegans nuclear envelope proteins emerin, MAN1, lamin and nucleoporins reveal unique timing of nuclear envelope breakdown during mitosis. Mol Biol Cell 11: 3089-3099.

 

 

 

return to top

Updated: 10/24/11

Johns Hopkins University School of Medicine
Department of Cell Biology
725 N. Wolfe Street, WBSB 114
Baltimore, MD 21205-2185
Director's Office: 410.502-6810 / FAX 410.614.9461  
**This site best when viewed in Mozilla Firefox**
  
Copyright © 2009 Johns Hopkins University Department of Cell Biology
All rights reserved. Contact webmaster