725 N. Wolfe Street
Baltimore MD 21205
We study the structure and function of the cell nucleus, ‘mothership’ of the human genome. We seek to understand how nuclear envelope (NE) membrane proteins interact with nuclear intermediate filament (‘lamina’) networks and other partners to collectively establish, protect and regulate the ‘customized’ 3D genome architecture unique to each cell type. Our research centers on three key components of nuclear lamina structure: lamins (e.g., lamin A and lamin C, encoded by LMNA), LEM-domain proteins (e.g., emerin, encoded by EMD), and BAF (Barrier to autointegration factor, encoded by BANF1). In addition to organizing and regulating chromatin during interphase, these proteins have active roles during exit from mitosis and early G1-phase, coalescing chromosomes and dynamically rebuilding nuclear structure and tissue-specific 3D genome architecture. Small (e.g., missense) mutations in these proteins can cause a bewildering variety of tissue-specific diseases including Emery-Dreifuss muscular dystrophy (EDMD), cardiomyopathy, lipodystrophy, diabetes and ‘accelerated aging’ (progeria syndromes), reflecting their diverse, and sometimes highly tissue-specific, roles in the nucleus. To provide foundational knowledge about lamin A/C interactions in native tissues, and to test the hypothesis that lamin A/C interactions are perturbed by chronic inflammation, we identified native lamin A/C-associated proteomes from three tissues— heart, skeletal muscle and brain— in aged (21-22 months) female control versus IL10tm (chronically inflamed) mice. We identified 502 candidate lamin A/C-associated proteins in native skeletal muscle, 340 candidates in heart, and over 2,400 in whole brain. Biochemical screens for lamin A or lamin C binding to peptide-arrayed candidates revealed direct binding of one or both lamins to 11 tested candidates, several of which were affected in the IL10tm mouse model of human frailty. These proteomes are valuable resources for further work to understand how lamin A and lamin C each function at the molecular level and influence disease risk in heart, skeletal muscle and brain. Independently, to understand their fundamentally unique roles after mitosis, we are collaborating with Karen Reddy (Dept. Biological Chemistry/Epigenetics Institute) and Robert N. Cole (Dept. Biological Chemistry/JHU Proteomics Core) to identify distinct lamin A-specific and lamin C-specific proteomes during mitotic exit and early G1-phase, when lamin C ‘surrounds’ heterochromatin in the nuclear interior, before re-associating with lamin A at the nuclear envelope.
Wang SM, Goguadze N, Kimura Y, Yasui Y, Pan B, Wang TY, Nakamura Y, Lin YT, Hogan QH, Wilson KL, Su TP and Wu HE (2021) Genomic action of sigma-1 receptor chaperone relates to neuropathic pain. Mol Neurobiol. 58:2523-41
Crews DC, Wilson KL, Sohn J, Kabacoff CM, Poynton SL, Murphy LR, Bolz J, Wolfe A, White PT, Will C, Collins C, Gauda E and Robinson DN (2020) Helping scholars overcome socioeconomic barriers to medical and biomedical careers: Creating a pipeline initiative. Teach Learn Med. 32:422-33.
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.