Nuclear lamins, laminopathies & adipose stem cells

Lipodystrophic laminopathies

Project leader: Nolwenn Briand

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, LMNC) and B-type lamins (LMNB1, LMNB2). Mutations in LMNA cause laminopathies, which include muscle dystrophies and lipodystrophies. Familial partial lipodystrophy of Dunnigan type (FPLD2), caused by the LMNA p.R482W mutation, affects adipose tissue in a fat depot-specific manner and leads to metabolic disorders.
We use patient cells and engineered adipose stem cells to address the impact of lipodystrophic LMNA mutations on adipogenic differentiation in upper and lower body adipose tissue.

Ongoing research:

  • Identification of determinants of nuclear envelope-chromatin interactions during lineage-specific differentiation and in laminopathy contexts
  • Impact of nuclear lamins on 3D genome architecture during adipogenic differentiation
  • Regulation of upper vs. lower body fat tissue expansion

 

Recent findings:

  • LIpodystrophic LMNA mutation deregulates the mesodermal inducer 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 miR-335 overexpression and impairement of adipogenic differentiation (Oldenburg et al. 2017 J Cell Biol  216, 2731-43)
  • Lipodystrophic LMNA mutation alters LADs and 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 post-translational modification N-acetylglucosamine (H2B-S112GlcNAc) , linking radial gene positioning to cellular metabolic state (Rønningen, Shah et al 2015 Genome Res 25, 1825-1835)
  • Fragile X-related protein 1 (FXR1) is a new 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)
  • Regulated association of LMNA with gene promoters during adipogenic differentiation (Lund et al. 2013 Genome Res 23, 1580-1589)