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Nuclear envelope, lamins and nucleoskeleton; Emery-Dreifuss muscular dystrophy
Within each human cell is a NUCLEUS, 'mothership' of the human genome and still the least-understood cellular structure. Chromosomes are enclosed by the nuclear envelope (NE) and communicate with the cytoplasm through Nuclear Pore Complexes (NPCs). The inner and outer membranes of the NE are mechanically connected by SUN-domain proteins and nesprins, which form LINC (links the nucleoskeleton and cytoskeleton) complexes. LINC complexes are anchored to nuclear intermediate filament (nuclear ‘lamina’) networks. Together the NE and nuclear lamina protect, organize and help regulate chromatin. Research in the Wilson lab centers on the three key components of nuclear lamina structure: lamins (encoded by LMNA, LMNB1, LMNB2), LEM-domain proteins (e.g., emerin, encoded by EMD), and BAF (Barrier to autointegration factor, encoded by BANF1). These proteins all bind each other directly, and are collectively required to organize and regulate chromatin, efficiently segregate chromosomes and rebuild nuclear structure after mitosis. Mutations in one or more of these proteins cause a variety of diseases including Emery-Dreifuss muscular dystrophy (EDMD), cardiomyopathy, lipodystrophy/diabetes and ‘accelerated aging’ (progeria syndromes). Loss of emerin typically causes X-linked recessive 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 proteins including A-type lamins, nesprin-1, nesprin-2, LUMA (a membrane protein that associates with emerin), and FHL1 (a muscle-relevant transcription factor). Since most of these proteins interact, defects in a mechano-transduction signaling complex that includes these proteins might contribute to disease. Current work aims to understand emerin’s role in mechanotransduction, how emerin and lamin A are regulated, and whether misregulation contributes to disease.
Arun AS, Eddings CR and Wilson KL (2019) Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine. Exp. Biol. Med. 244:1354-1361.
Dharmaraj T, Guan YC, Liu J, Badens C, Gaborit B and Wilson KL (2019) Rare BANF1 alleles and relatively frequent EMD alleles including ‘healthy lipid’ emerin p.D149H in the ExAC cohort. Front. Cell Dev. Biol. 7:48
Wilson KL (2018) Nuclear import pathway key to rescuing dominant progerin phenotypes. Science Signaling 11(537)
Dharmaraj T and Wilson KL (2017) How chromosomes unite. Nature 551:568-9.
Simon DN, Wriston A, Florwick A, Fan Q, Dharmaraj T, Shabanowitz J, Peterson SB, Gruenbaum Y, Carlson CR, Grønning-Wang LM, Hunt DF and Wilson KL (2018) OGT (O-GlcNAc transferase) selectively modifies multiple residues unique to lamin A. Cells 7:44
Florwick A, Dharmaraj T, Jurgens J, Valle D and Wilson KL (2017) LMNA sequences of 60,706 unrelated individuals reveal 132 novel missense variants in A-type lamins and suggest a link between variant p.G602S and type 2 diabetes. Frontiers in Genetics 8:79.
Bar DZ, Davidovich M, Lamm AT, Zer H, Wilson KL and Gruenbaum Y (2014) BAF-1 mobility is regulated by environmental stresses. Mol. Biol. Cell 25:1127-36.
Berk JM, Simon DN, Jenkins-Houk CR, Westerbeck JW, Gronning-Wang LM, Carlson CR and Wilson KL (2014) The molecular basis of emerin-emerin and emerin-BAF interactions. J. Cell Science 127:3956-3969.
Wozniak M, Baker BM, Chen C and Wilson KL (2013) Emerin-binding transcription factor Lmo7 is regulated by association with p130Cas at focal adhesions. PeerJ e134
Berk JM, Maitra S, Dawdy AW, Shabanowitz J, Hunt DJ and Wilson KL (2013) O-GlcNAc regulates emerin binding to BAF in a chromatin- and lamin B-enriched ‘niche’. J. Biol. Chem. 288:30192-209.
Simon DN and Wilson KL (2013) Partners and posttranslational modifications of nuclear lamins. Chromosoma.
Simon DN, Domaradzki T, Hofmann WA and Wilson KL (2013) Lamin A tail modification by SUMO1 is disrupted by familial partial lipodystrophy-causing mutations. Mol. Biol. Cell 24:342-50.
Gjerstorff MF, Rцsner HI, Pedersen CB, Greve KB, Schmidt S, Wilson KL, Mollenhauer J, Besir H, Poulsen FM, Mшllegaard NE and Ditzel HJ (2012) GAGE cancer-germline antigens are recruited to the nuclear envelope by germ cell-less(GCL). PloS One 7:e45819.
Barkan R, Zahand AJ, Sarabi K, Lamm AT, Feinstein N, Haithcock E, Wilson KL, Liu J and Gruenbaum Y (2012) Ce-emerin and LEM-2: essential roles in Caenorhabditis elegans development, muscle function and mitosis. Mol Biol Cell 23:543-552
Simon DN and Wilson KL (2011) The nucleoskeleton as a dynamic genome-associated ‘network of networks’. Nature Reviews Mol. Cell. Biol. 12:695-708.
Wilson KL and Dawson SC (2011) Functional evolution of nuclear structure. J Cell Biology 195:171-181. PubMed Reference Montes de Oca RM, Andreassen PR and Wilson KL (2011) Barrier to Autointegration Factor influences specific histone modifications. Nucleus 2:580-90.
Simon DN, Zastrow MS, Wilson KL (2010) Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail. Nucleus 1:264-72.
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. Chem. 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.
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 Molecular Genetics 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, 3290-95.
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. Biological Chemistry 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.