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Hum Mol Genet. 2015 Apr 1;24(7):2096-109. doi: 10.1093/hmg/ddu728. Epub 2014 Dec 18.

The p.R482W substitution in A-type lamins deregulates SREBP1 activity in Dunnigan-type familial partial lipodystrophy.

Author information

1
Unit of Functional and Adaptive Biology (BFA), Université Paris Diderot-Paris 7 Affiliated with CNRS, 4 rue Marie-Andrée Lagroua Weill-Halle, Paris Cedex 13 75205, France.
2
Université Paris Diderot, Matière et Systèmes Complexes, CNRS UMR 7057, 10 rue Alice Domon et Leonie Duquet, Paris Cedex 13 75205, France, Physics Department, Université Pierre et Marie Curie, Paris UFR925, France.
3
Faculté de Médecine Pierre et Marie Curie, Inserm, UMR S938, Centre de Recherche Saint-Antoine, 27 rue Chaligny, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 6, UMR S938, Paris F-75005, France, ICAN, Institute of Cardiometabolism and Nutrition, Paris F-75013, France.
4
Faculté de Médecine Pierre et Marie Curie, Inserm, UMR S938, Centre de Recherche Saint-Antoine, 27 rue Chaligny, Paris F-75012, France, Sorbonne Universités, UPMC Univ Paris 6, UMR S938, Paris F-75005, France, ICAN, Institute of Cardiometabolism and Nutrition, Paris F-75013, France, Laboratoire Commun de Biologie et Génétique Moléculaires, AP-HP, Hôpital Saint-Antoine, Paris F-75012, France and.
5
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, Oslo 0317, Norway.
6
Unit of Functional and Adaptive Biology (BFA), Université Paris Diderot-Paris 7 Affiliated with CNRS, 4 rue Marie-Andrée Lagroua Weill-Halle, Paris Cedex 13 75205, France, brigitte.buendia@univ-paris-diderot.fr.

Abstract

Nuclear lamins are involved in many cellular functions due to their ability to bind numerous partners including chromatin and transcription factors, and affect their properties. Dunnigan type familial partial lipodystrophy (FPLD2; OMIM#151660) is caused in most cases by the A-type lamin R482W mutation. We report here that the R482W mutation affects the regulatory activity of sterol response element binding protein 1 (SREBP1), a transcription factor that regulates hundreds of genes involved in lipid metabolism and adipocyte differentiation. Using in situ proximity ligation assays (PLA), reporter assays and biochemical and transcriptomic approaches, we show that interactions of SREBP1 with lamin A and lamin C occur at the nuclear periphery and in the nucleoplasm. These interactions involve the Ig-fold of A-type lamins and are favored upon SREBP1 binding to its DNA target sequences. We show that SREBP1, LMNA and sterol response DNA elements form ternary complexes in vitro. In addition, overexpression of A-type lamins reduces transcriptional activity of SREBP1. In contrast, both overexpression of LMNA R482W in primary human preadipocytes and endogenous expression of A-type lamins R482W in FPLD2 patient fibroblasts, reduce A-type lamins-SREBP1 in situ interactions and upregulate a large number of SREBP1 target genes. As this LMNA mutant was previously shown to inhibit adipogenic differentiation, we propose that deregulation of SREBP1 by mutated A-type lamins constitutes one underlying mechanism of the physiopathology of FPLD2. Our data suggest that SREBP1 targeting molecules could be considered in a therapeutic context.

PMID:
25524705
DOI:
10.1093/hmg/ddu728
[Indexed for MEDLINE]

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