Nuclear lamins and lipodystrophic laminopathies
Using patient cells and engineered adipose tissue stem cells, we mechanistically investigate the deregulation of adipogenic differentiation by lipodystrophic LMNA mutations in upper and lower body adipose tissue.
About the project
The nuclear envelope regulates gene expression through dynamic interactions with chromatin. It consists of a double nuclear membrane, nuclear pores and the nuclear lamina, a meshwork of A-type lamins (LMNA/C) and B-type lamins (LMNB1, LMNB2). Mutations in LMNA cause laminopathies, including lipodystrophies.
Familial partial lipodystrophy of Dunnigan type (FPLD2), caused by the host-spot LMNA p.R482W mutation, affects adipose tissue in a fat depot-specific manner and leads to severe metabolic disorders.
Ongoing research
- Molecular regulation of upper vs. lower body adipose tissue expansion
- Role of LMNA on genome conformation and gene regulation in adipose stem cells
- Impacts of lipodystrophic LMNA mutations on spatial genome organization and function
Outcomes/Recent findings
- Lipodystrophic LMNA mutation deregulates T/Brachyury and early vascular differentiation gene networks (Briand, Guénantin et al. 2018 Hum Mol Genet 27, 1447-1459)
- Lipodystrophic LMNA mutation deregulates epigenetic and spatial conformation of anti-adipogenic MIR335 locus, leading to impairment of adipose differentiation (Oldenburg et al. 2017 J Cell Biol 216, 2731-2743)
- Lipodystrophic LMNA mutation alters radial positioning of loci in patient cells (Paulsen et al. 2017 Genome Biol 18, 21)
- Patterning of LMNA LADs by domains of histone H2B modified by the nutrient-sensing modification N-acetylglucosamine (H2B-S112GlcNAc), linking chromatin topology to metabolism (Rønningen et al 2015 Genome Res 25, 1825-1835)
- Deregulation of Fragile X-related protein 1 by a lipodystrophic LMNA mutation leads to induction of myogenic gene expression in pre-adipocytes (Oldenburg et al 2014 Hum Mol Genet 23, 1151-1162)
- Dynamic association of LMNA with gene promoters during adipose differentiation (Lund et al. 2013 Genome Res 23, 1580-1589)
Funding
The University of Oslo, The Research Council of Norway, South-East Norway Regional Health Authorities
Collaborations
- Jøran Hjelmesæth and Jens Hertel, Morbid Obesity Center, Vestfold Hospital Trust, Tønsberg, Norway
- Yvonne Böttcher, Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Norway
- Corinne Vigouroux, Hôpital Saint Antoine, INSERM, Paris, France
- Fredrick Karpe, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, UK
- Anna Kostareva, Almazov Research Center, St. Petersburg, Russia