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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

 Yong-Sun Maeng  ;  Ga-Hyun Lee  ;  Seung-Il Choi  ;  Kyu Seo Kim  ;  Eung Kweon Kim 
 BMC MEDICAL GENOMICS, Vol.8 : 74, 2015 
Journal Title
Issue Date
Cornea/cytology ; Cornea/pathology ; Corneal Dystrophies, Hereditary/genetics* ; Corneal Dystrophies, Hereditary/metabolism ; Corneal Dystrophies, Hereditary/pathology ; Extracellular Matrix/metabolism* ; Extracellular Matrix/secretion ; Extracellular Matrix Proteins/genetics* ; Extracellular Matrix Proteins/secretion ; Fibroblasts/cytology* ; Fibroblasts/pathology* ; Gene Expression Regulation* ; Gene Knockdown Techniques ; Histone-Lysine N-Methyltransferase/deficiency ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry ; Histones/metabolism* ; Homozygote ; Humans ; Lysine/metabolism ; Methylation ; Myeloid-Lymphoid Leukemia Protein/deficiency ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Protein Transport ; Smad3 Protein/metabolism ; Transcription, Genetic ; Transforming Growth Factor beta/genetics* ; Transforming Growth Factor beta/secretion ; Transforming Growth Factor beta1/metabolism
GCD2 ; TGFBIp ; Extracellular matrix ; Histone methylation
BACKGROUND: 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.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Maeng, Yong Sun(맹용선) ORCID logo https://orcid.org/0000-0003-1694-8405
Lee, Ga Hyun(이가현)
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
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