Nuclear lamins, laminopathies & adipose tissue regulation

Nuclear lamins, laminopathies & adipose tissue regulation

Nolwenn Briand (leader), Evdokiia Potolitsyna, Louise Petersen, Julia Madsen-Østerbye, Anita Sørensen

The nuclear envelope regulates gene expression by interacting 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, which include 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.
Using patient cells and engineered adipose stem cells, we mechanistically investigate the deregulation of adipogenic differentiation by lipodystrophic LMNA mutations in upper and lower body adipose tissue.

Ongoing research:

• Regulation of upper vs. lower body fat tissue expansion
• Determinants of nuclear lamin-chromatin interactions and spatial chromatin postioning during adipogenic differentiation
• Role of LMNA on spatial genome conformation and gene regulation in adipose stem cells
• Impact of LMNA mutations on spatial genome organization and function

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 impairement 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 H2B modified by the nutrient-sensing  modification N-acetylglucosamine (H2B-S112GlcNAc), linking radial chromatin positioning to cell metabolic state (Rønningen et al 2015 Genome Res 25, 1825-1835)
• Fragile X-related protein 1 (FXR1) is a LMNA binding partner; its deregulation 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)
• Association of LMNA with promoters during adipogenic differentiation (Lund et al. 2013 Genome Res 23, 1580-1589)