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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Epigenetic silencing of lysyl oxidase-like-1 through DNA hypermethylation in an autosomal recessive cutis laxa case
Journal of Investigative Dermatology, Volume 130, No. 11, Year 2010
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Description
We have recently reported a case of cutis laxa caused by a fibulin-5 missense mutation (p.C217R). Skin fibroblasts from this individual showed an abnormal pattern of expression of several genes coding for elastic fiber-related proteins, including lysyl oxidase-like-1 (LOXL1). In this study we intended to elucidate the mechanism responsible for LOXL1 downregulation in these fibulin-5-mutant cells. We identified a proximal region (442/342) of the human LOXL1 promoter in which two binding sites for the transcription factor specific protein 1 (Sp-1) are required for gene activity in normal fibroblasts. Binding of Sp-1 to these sequences was dramatically reduced within cutis laxa cells, although Sp-1 expression was normal. Further analysis of the promoter sequence found increased methylation levels in cutis laxa cells compared with cells from unaffected individuals. When DNA methyltransferase activity was transiently inhibited in cutis laxa cells using the 5-aza-2′-deoxycytidine, we found a significant increase in LOXL1 expression. In conclusion, besides changes caused by the fibulin-5 mutation, LOXL1 gene regulation is affected by an epigenetic mechanism that can be reversed by an inhibitor of DNA methyltransferase activity. It is not yet known whether LOXL1 gene expression is affected in all cases of cutis laxa arising from fibulin-5 mutation. © 2010 The Society for Investigative Dermatology.
Authors & Co-Authors
Debret, Romain
France, Villeurbanne
Université Claude Bernard Lyon 1
Cenizo, Valérie
France, Lyon
Basf Beauty Care Solutions France S.a.s
Aimond, Géraldine
France, Villeurbanne
Université Claude Bernard Lyon 1
André-Frei, Valérie
France, Lyon
Basf Beauty Care Solutions France S.a.s
Devillers, Martine
France, Evry
Association Française Contre Les Myopathies
Rouvet, Isabelle
France, Lyon
Centre de Biotechnologie Cellulaire
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Damour, Odile
France, Villeurbanne
Université Claude Bernard Lyon 1
Sommer, Pascal
France, Villeurbanne
Université Claude Bernard Lyon 1
Statistics
Citations: 19
Authors: 9
Affiliations: 5
Identifiers
Doi:
10.1038/jid.2010.186
ISSN:
0022202X
e-ISSN:
15231747
Research Areas
Cancer
Genetics And Genomics