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Histone methylation levels correlate with TGFBIp and extracellular matrix gene expression in normal and granular corneal dystrophy type 2 corneal fibroblasts

DC FieldValueLanguage
dc.contributor.author김응권-
dc.contributor.author맹용선-
dc.contributor.author이가현-
dc.contributor.author최승일-
dc.date.accessioned2018-03-26T16:43:16Z-
dc.date.available2018-03-26T16:43:16Z-
dc.date.issued2015-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/156752-
dc.description.abstractBACKGROUND: TGFβ1-induced expression of transforming growth factor β-induced protein (TGFBIp) and extracellular matrix (ECM) genes plays a major role in the development of granular corneal dystrophy type 2 (GCD2: also called Avellino corneal dystrophy). Although some key transcription factors are known, the epigenetic mechanisms modulating TGFBIp and ECM expression remain unclear. We examined the role of chromatin markers such as histone H3 lysine methylation (H3Kme) in TGFβ1-induced TGFBIp and ECM gene expression in normal and GCD2-derived human corneal fibroblasts. METHODS: Wild-type (n = 3), GCD2-heterozygous (n = 1), and GCD2-homozygous (n = 3) primary human corneal fibroblasts were harvested from human donors and patients prepared. Microarray and gene-expression profiling, Chromatin immunoprecipitation microarray analysis, and Methylated DNA isolation assay-assisted CpG microarrays was performed in Wild-type and GCD2-homozygous human cells. RESULTS: Transcription and extracellular-secretion levels of TGFBIp were high in normal cells compared with those in GCD2-derived cells and were related to H3K4me3 levels but not to DNA methylation over the TGFBI locus. TGFβ1 increased the expression of TGFBIp and the ECM-associated genes connective tissue growth factor, collagen-α2[Ι], and plasminogen activator inhibitor-1 in normal corneal fibroblasts. Increased levels of gene-activating markers (H3K4me1/3) and decreased levels of repressive markers (H3K27me3) at the promoters of those gene accompanied the changes in expression. TGFβ1 also increased recruitment of the H3K4 methyltransferase MLL1 and of SET7/9 and also the binding of Smad3 to the promoters. Knockdown of both MLL1 and SET7/9 significantly blocked the TGFβ1-induced gene expression and inhibited TGFβ1-induced changes in promoter H3K4me1/3 levels. Those effects were very weak, however, in GCD2-derived corneal fibroblasts. CONCLUSIONS: Taken together, the results show the functional role of H3K4me in TGFβ1-mediated TGFBIp and ECM gene expression in corneal fibroblasts. Pharmacologic and other therapies that regulate these modifications could have potential cornea-protective effects for granular corneal dystrophy.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherBioMed Central-
dc.relation.isPartOfBMC MEDICAL GENOMICS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHCornea/cytology-
dc.subject.MESHCornea/pathology-
dc.subject.MESHCorneal Dystrophies, Hereditary/genetics*-
dc.subject.MESHCorneal Dystrophies, Hereditary/metabolism-
dc.subject.MESHCorneal Dystrophies, Hereditary/pathology-
dc.subject.MESHExtracellular Matrix/metabolism*-
dc.subject.MESHExtracellular Matrix/secretion-
dc.subject.MESHExtracellular Matrix Proteins/genetics*-
dc.subject.MESHExtracellular Matrix Proteins/secretion-
dc.subject.MESHFibroblasts/cytology*-
dc.subject.MESHFibroblasts/pathology*-
dc.subject.MESHGene Expression Regulation*-
dc.subject.MESHGene Knockdown Techniques-
dc.subject.MESHHistone-Lysine N-Methyltransferase/deficiency-
dc.subject.MESHHistone-Lysine N-Methyltransferase/genetics-
dc.subject.MESHHistone-Lysine N-Methyltransferase/metabolism-
dc.subject.MESHHistones/chemistry-
dc.subject.MESHHistones/metabolism*-
dc.subject.MESHHomozygote-
dc.subject.MESHHumans-
dc.subject.MESHLysine/metabolism-
dc.subject.MESHMethylation-
dc.subject.MESHMyeloid-Lymphoid Leukemia Protein/deficiency-
dc.subject.MESHMyeloid-Lymphoid Leukemia Protein/genetics-
dc.subject.MESHMyeloid-Lymphoid Leukemia Protein/metabolism-
dc.subject.MESHProtein Transport-
dc.subject.MESHSmad3 Protein/metabolism-
dc.subject.MESHTranscription, Genetic-
dc.subject.MESHTransforming Growth Factor beta/genetics*-
dc.subject.MESHTransforming Growth Factor beta/secretion-
dc.subject.MESHTransforming Growth Factor beta1/metabolism-
dc.titleHistone methylation levels correlate with TGFBIp and extracellular matrix gene expression in normal and granular corneal dystrophy type 2 corneal fibroblasts-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Ophthalmology-
dc.contributor.googleauthorYong-Sun Maeng-
dc.contributor.googleauthorGa-Hyun Lee-
dc.contributor.googleauthorSeung-Il Choi-
dc.contributor.googleauthorKyu Seo Kim-
dc.contributor.googleauthorEung Kweon Kim-
dc.identifier.doi10.1186/s12920-015-0151-8-
dc.contributor.localIdA00831-
dc.contributor.localIdA01346-
dc.contributor.localIdA02637-
dc.contributor.localIdA04099-
dc.relation.journalcodeJ00362-
dc.identifier.eissn1755-8794-
dc.identifier.pmid26553048-
dc.subject.keywordGCD2-
dc.subject.keywordTGFBIp-
dc.subject.keywordExtracellular matrix-
dc.subject.keywordHistone methylation-
dc.contributor.alternativeNameKim, Eung Kweon-
dc.contributor.alternativeNameMaeng, Yong Sun-
dc.contributor.alternativeNameLee, Ga Hyun-
dc.contributor.alternativeNameChoi, Seung Il-
dc.contributor.affiliatedAuthorKim, Eung Kweon-
dc.contributor.affiliatedAuthorMaeng, Yong Sun-
dc.contributor.affiliatedAuthorLee, Ga Hyun-
dc.contributor.affiliatedAuthorChoi, Seung Il-
dc.citation.volume8-
dc.citation.startPage74-
dc.identifier.bibliographicCitationBMC MEDICAL GENOMICS, Vol.8 : 74, 2015-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소) > 1. Journal Papers

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