Genetics, Epigenetics & Gene Regulation | Nucleus & Chromosome Biology
Lamins in nuclear organization and human disease
Lamins form a stable scaffold structure at the nuclear envelope, the lamina, and are also found throughout the nucleoplasm. They determine mechanical properties of the nucleus and are involved in chromatin regulation and gene expression. Lamin mutations cause human diseases ranging from muscular dystrophy to premature-aging syndromes. We aim at understanding molecular mechanisms of lamin functions in nuclear organization and chromatin regulation during differentiation and their...more
Lamins form a stable scaffold structure at the nuclear envelope, the lamina, and are also found throughout the nucleoplasm. They determine mechanical properties of the nucleus and are involved in chromatin regulation and gene expression. Lamin mutations cause human diseases ranging from muscular dystrophy to premature-aging syndromes. We aim at understanding molecular mechanisms of lamin functions in nuclear organization and chromatin regulation during differentiation and their role in diseases. In particular, we investigate i) how lamin-binding proteins affect lamin dynamics and functions, ii) how these proteins crontrol lamin-chromatin interactions, and iii) how these processes are affected by lamin disease mutations.
We have been studying lamin-interacting proteins of the LEM (LAP-Emerin-MAN1) protein family, which bind chromatin via their LEM motif. While most LEM proteins localize to the inner nuclear membrane, Lamina-associated polypeptide 2α (LAP2α) is in the nucleoplasm and binds lamins in the nuclear interior. In LAP2α-deficient mice we found that LAP2α stabilizes lamins in the nuclear interior and regulates proliferation and differentiation of tissue stem cells, but mechanistic details are unknown and are currently investigated.
Chromatin regulation by lamins in health and disease (FWF grant P26492-B20).
The lamina interacts with heterochromatic genomic regions, termed lamina-associated domains. By chromatin immunoprecipitation we found that LAP2a and lamins in the nuclear interior associate with open euchromatic regions, and LAP2a loss affects lamin-chromatin interactions, epigenetic profiles and gene expression (Fig. 1). This novel role of LAP2a and lamins in gene regulation may also be involved in the progeria premature ageing disease phenotype. Expression of the progeria-linked lamin mutant, leads to loss of LAP2a and lamins in the nuclear interior and affects expression of extracellular matrix genes, while ectopic LAP2a rescues this phenoptype. We currently investigate the potential mechanisms involved.
Endothelial dysfunction and cardiovascular disease in progeria premature aging diseasae (Progeria research Foundation grant PRF 2016-64).
Progeria disease is characterized by severe symptoms resembling features of premature aging, including cardiovascular disease that leads to myocardial infarction. In order to study the molecular basis of progeria-linked cardiovascular disease, we generated a mouse model expressing the lamin mutant in vascular endothelial cells. We find heart left ventricular hypertrophy and pro-atherogenic changes, such as attenuated shear stress response and mechanosignaling by the nucleus. We will investigate these defects at molecular level and aim at identifying new (pro-atherogenic) pathways and components as potential targets for diagnosis and therapy.
See movie: Investigating atherosclerosis in progeriaclose
Gesson, Kevin; Rescheneder, Philipp; Skoruppa, Michael P; von Haeseler, Arndt; Dechat, Thomas; Foisner, Roland (2016). A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. GENOME RES;26(4):462-73. PMID: 26798136
Vidak, Sandra, Kubben, Nard, Dechat, Thomas and Roland Foisner
(2015). Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2α (LAP2α) through expression of extracellular matrix proteins GENE DEV;29(19):2022-2036. PMID: 26443848
Gruenbaum, Yosef; Foisner, Roland (2015). Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annual review of biochemistry.;84:131-64. PMID: 25747401
FWF Stand Alone Projects
Chromatin organization by lamina-independent lamins (P26492-B20)
Progeria Research Foundation project
Contribution of endothelial cell dysfunction to cardiovascular disease in progeria (PRF 2016-64)