A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus
| Autor: | Jan Øivind Moskaug, Anita L. Sørensen, Anja R. Oldenburg, Philippe Collas, Nolwenn Briand, Inswasti Cahyani, Akshay Shah |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities integumentary system Mutant MicroRNA Gene Cell Biology Biology Molecular biology Chromatin LMNA 03 medical and health sciences 030104 developmental biology embryonic structures Gene expression Epigenetics Enhancer Lamin |
| Zdroj: | Journal of Cell Biology. 216:2731-2743 |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.201701043 |
| Popis: | Mutations in the Lamin A/C (LMNA) gene-encoding nuclear LMNA cause laminopathies, which include partial lipodystrophies associated with metabolic syndromes. The lipodystrophy-associated LMNA p.R482W mutation is known to impair adipogenic differentiation, but the mechanisms involved are unclear. We show in this study that the lamin A p.R482W hot spot mutation prevents adipogenic gene expression by epigenetically deregulating long-range enhancers of the anti-adipogenic MIR335 microRNA gene in human adipocyte progenitor cells. The R482W mutation results in a loss of function of differentiation-dependent lamin A binding to the MIR335 locus. This impairs H3K27 methylation and instead favors H3K27 acetylation on MIR335 enhancers. The lamin A mutation further promotes spatial clustering of MIR335 enhancer and promoter elements along with overexpression of the MIR355 gene after adipogenic induction. Our results link a laminopathy-causing lamin A mutation to an unsuspected deregulation of chromatin states and spatial conformation of an miRNA locus critical for adipose progenitor cell fate. |
| Databáze: | OpenAIRE |
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