We are interested in nuclear organization during the cell cycle and differentiation, focusing on the role of lamins and lamin-binding proteins in mechano-signaling and in chromatin organization. While most studies on lamins focus on the lamina, the scaffold structure at the nuclear periphery of metazoan cells, we have described a mobile lamin pool in the nuclear interior. We identified proteins and pathways regulating the mobile lamin pool and showed that nucleoplasmic lamins have essential role in chromatin regulation and gene expression, thereby regulating stem cell differentiation. Currently we are analyzing lamin-linked pathways regulating the tissue specific localization of genes within the nucleus. We also study the molecular mechnisms of lamin-linked diseases (laminopathies) in cells and animal models and found an interesting role of nucleoplasmic lamins in the premature aging disease progeria. As the life-threatening pathology in progeria is a sever cardiovascular disease phenotype leading to early heart failure, we generated disease mouse model expressing the disease-causing lamin A mutant (progerin) in vascular endothelial cells, to shed light on the molecular contribution of vascular cells to the cardiovascular pathology. We find an impaired flow shear stress response and in mechno-signaling in progerin-expressing cells and currently analyze the mechanistic details.
We use a broad range of biochemical protein assays and molceular and cell biological approaches to study molecular pathways in vitro, including protein expression, gene knockdown and knock out by CRISPR/Cas9,chromatin immunoprecipitation, proteome wide interactome analysis and a range of modern (superresolution) fluorescence microscopic approaches.
We also generate and analyse transgenic mouse models and tissues (epidermis, striated muscle, colon, hematopoietic cells) and generate primary cell culture differentiation models.
Superresolution microscopy, (cryo) electron microscopy, chromatin analyses, clinical research involving patients and therapeutic approaches.
1. Gesson K, Rescheneder P, Skoruppa MP, von Haeseler A, Dechat T, Foisner R. (2016) A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2alpha. Genome Res. 2016, 26(4):462-73. doi: 10.1101/gr.196220.115.
2. Vidak, S., , Kubben, N., Dechat, T and Foisner, R. (2015) Proliferation of progeria cells is enhanced by lamina-associated polypeptide (LAP) 2a through expression of extracellular matrix proteins. Genes Dev, 29(19):2022-36. doi:10.1101/gad.263939.115.
3. Osmanagic-Myers, Dechat, T and Foisner R (2015) Lamins at the crossroads of mechanosignaling. Genes Dev. 29, 225 – 237. doi: 10.1101/gad.255968.114
4. Gotic I, Schmidt WM, Biadasiewicz K, Leschnik M, Spilka R, Braun J, Stewart CL, Foisner R. 2010. Loss of LAP2alpha Delays Satellite Cell Differentiation and Affects Postnatal Fiber Type Determination. Stem Cells. 2010, 28:480-488.
5. Naetar, N., B. Korbei, S. Kozlov, M.A. Kerenyi, D. Dorner, R. Kral, I. Gotic, P. Fuchs, T.V. Cohen, R. Bittner, C.L. Stewart, and R. Foisner. 2008. Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation. Nat Cell Biol. 10:1341-1348.