Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression

Akihiro Umezawa, Hideyuki Yamamoto, Katherine Rhodes, Michael Klemsz, Richard A. Maki, Robert G. Oshima

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The activities of ETS transcription factors are modulated by posttranscriptional modifications and cooperation with other proteins. Another factor which could alter the regulation of genes by ETS transcription factors is DNA methylation of their cognate binding sites. The optimal activity of the keratin 18 (K18) gene is dependent upon an ETS binding site within an enhancer region located in the first intron. The methylation of the ETS binding site was correlated with the repression of the K18 gene in normal human tissues and in K18 transgenic mouse tissues. Neither recombinant ETS2 nor endogenous spleen ETS binding activities bound the methylated site effectively. Increased expression of the K18 gene in spleens of transgenic mice by use of an alternative, cryptic promoter 700 bp upstream of the enhancer resulted in modestly decreased methylation of the K18 ETS site and increased RNA expression. Expression in transgenic mice of a mutant K18 gene, which was still capable of activation by ETS factors but was no longer a substrate for DNA methylation of the ETS site, was fivefold higher in spleen and heart. However, expression in other organs such as liver and intestine was similar to that of the wild-type gene. This result suggests that DNA methylation of the K18 ETS site may be functionally important in the tissue- specific repression of the K18 gene. Epigenetic modification of the binding sites for some ETS transcription factors may result in a refractory transcriptional response even in the presence of necessary trans-acting activities.

Original languageEnglish
Pages (from-to)4885-4894
Number of pages10
JournalMolecular and Cellular Biology
Volume17
Issue number9
StatePublished - Sep 1997

Fingerprint

Keratin-18
Introns
Methylation
Genes
DNA Methylation
Binding Sites
Transgenic Mice
Transcription Factors
Spleen
Epigenomics
Intestines
RNA
Liver

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression. / Umezawa, Akihiro; Yamamoto, Hideyuki; Rhodes, Katherine; Klemsz, Michael; Maki, Richard A.; Oshima, Robert G.

In: Molecular and Cellular Biology, Vol. 17, No. 9, 09.1997, p. 4885-4894.

Research output: Contribution to journalArticle

Umezawa, Akihiro ; Yamamoto, Hideyuki ; Rhodes, Katherine ; Klemsz, Michael ; Maki, Richard A. ; Oshima, Robert G. / Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression. In: Molecular and Cellular Biology. 1997 ; Vol. 17, No. 9. pp. 4885-4894.
@article{3df052006cc54977acf5b53953c149fb,
title = "Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression",
abstract = "The activities of ETS transcription factors are modulated by posttranscriptional modifications and cooperation with other proteins. Another factor which could alter the regulation of genes by ETS transcription factors is DNA methylation of their cognate binding sites. The optimal activity of the keratin 18 (K18) gene is dependent upon an ETS binding site within an enhancer region located in the first intron. The methylation of the ETS binding site was correlated with the repression of the K18 gene in normal human tissues and in K18 transgenic mouse tissues. Neither recombinant ETS2 nor endogenous spleen ETS binding activities bound the methylated site effectively. Increased expression of the K18 gene in spleens of transgenic mice by use of an alternative, cryptic promoter 700 bp upstream of the enhancer resulted in modestly decreased methylation of the K18 ETS site and increased RNA expression. Expression in transgenic mice of a mutant K18 gene, which was still capable of activation by ETS factors but was no longer a substrate for DNA methylation of the ETS site, was fivefold higher in spleen and heart. However, expression in other organs such as liver and intestine was similar to that of the wild-type gene. This result suggests that DNA methylation of the K18 ETS site may be functionally important in the tissue- specific repression of the K18 gene. Epigenetic modification of the binding sites for some ETS transcription factors may result in a refractory transcriptional response even in the presence of necessary trans-acting activities.",
author = "Akihiro Umezawa and Hideyuki Yamamoto and Katherine Rhodes and Michael Klemsz and Maki, {Richard A.} and Oshima, {Robert G.}",
year = "1997",
month = "9",
language = "English",
volume = "17",
pages = "4885--4894",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "9",

}

TY - JOUR

T1 - Methylation of an ETS site in the intron enhancer of the keratin 18 gene participates in tissue-specific repression

AU - Umezawa, Akihiro

AU - Yamamoto, Hideyuki

AU - Rhodes, Katherine

AU - Klemsz, Michael

AU - Maki, Richard A.

AU - Oshima, Robert G.

PY - 1997/9

Y1 - 1997/9

N2 - The activities of ETS transcription factors are modulated by posttranscriptional modifications and cooperation with other proteins. Another factor which could alter the regulation of genes by ETS transcription factors is DNA methylation of their cognate binding sites. The optimal activity of the keratin 18 (K18) gene is dependent upon an ETS binding site within an enhancer region located in the first intron. The methylation of the ETS binding site was correlated with the repression of the K18 gene in normal human tissues and in K18 transgenic mouse tissues. Neither recombinant ETS2 nor endogenous spleen ETS binding activities bound the methylated site effectively. Increased expression of the K18 gene in spleens of transgenic mice by use of an alternative, cryptic promoter 700 bp upstream of the enhancer resulted in modestly decreased methylation of the K18 ETS site and increased RNA expression. Expression in transgenic mice of a mutant K18 gene, which was still capable of activation by ETS factors but was no longer a substrate for DNA methylation of the ETS site, was fivefold higher in spleen and heart. However, expression in other organs such as liver and intestine was similar to that of the wild-type gene. This result suggests that DNA methylation of the K18 ETS site may be functionally important in the tissue- specific repression of the K18 gene. Epigenetic modification of the binding sites for some ETS transcription factors may result in a refractory transcriptional response even in the presence of necessary trans-acting activities.

AB - The activities of ETS transcription factors are modulated by posttranscriptional modifications and cooperation with other proteins. Another factor which could alter the regulation of genes by ETS transcription factors is DNA methylation of their cognate binding sites. The optimal activity of the keratin 18 (K18) gene is dependent upon an ETS binding site within an enhancer region located in the first intron. The methylation of the ETS binding site was correlated with the repression of the K18 gene in normal human tissues and in K18 transgenic mouse tissues. Neither recombinant ETS2 nor endogenous spleen ETS binding activities bound the methylated site effectively. Increased expression of the K18 gene in spleens of transgenic mice by use of an alternative, cryptic promoter 700 bp upstream of the enhancer resulted in modestly decreased methylation of the K18 ETS site and increased RNA expression. Expression in transgenic mice of a mutant K18 gene, which was still capable of activation by ETS factors but was no longer a substrate for DNA methylation of the ETS site, was fivefold higher in spleen and heart. However, expression in other organs such as liver and intestine was similar to that of the wild-type gene. This result suggests that DNA methylation of the K18 ETS site may be functionally important in the tissue- specific repression of the K18 gene. Epigenetic modification of the binding sites for some ETS transcription factors may result in a refractory transcriptional response even in the presence of necessary trans-acting activities.

UR - http://www.scopus.com/inward/record.url?scp=0030744463&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030744463&partnerID=8YFLogxK

M3 - Article

C2 - 9271368

AN - SCOPUS:0030744463

VL - 17

SP - 4885

EP - 4894

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 9

ER -