title: Epigenetic silencing of lysyl oxidase-like-1 through DNA hypermethylation in an autosomal recessive cutis laxa case.
abstract: 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.
authors.affiliation: Institut de Biologie et Chimie des Protéines, Université Claude Bernard, Lyon, France. r.debret@ibcp.fr
authors.forename: Romain
authors.initials: R
authors.lastname: Debret
authors.forename: Valérie
authors.initials: V
authors.lastname: Cenizo
authors.forename: Géraldine
authors.initials: G
authors.lastname: Aimond
authors.forename: Valérie
authors.initials: V
authors.lastname: André
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouvet
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Odile
authors.initials: O
authors.lastname: Damour
authors.forename: Pascal
authors.initials: P
authors.lastname: Sommer
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D003483:Cutis Laxa / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D016329:Sp1 Transcription Factor; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human