GSE98675
The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks
The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigantype (FPLD2), a lipodystrophic syndrome complicated by early-onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482Wassociated FPLD2. Correction of the LMNA mutation ameliorates R482W-associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex PRC2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multitissue pathogenic phenotypes. Overall design: RNA-seq data pertain to examination of expression profiles of 1) iPS cells derived from patients with Familial Partial Lipodystrophy of Dunnigan-type (FPLD2) with the LMNA p.R482W mutation and 2) FPLD2 patient-derived iPS cells in which the LMNA mutation has been repaired -- both during mesodermal differentiation from day 0 to day 4. ChIP-seq data pertain to ChIP of lamin A/C (LMNA) and lamin B1 (LMNB1) from cultured FPLD2 patient fibroblasts.