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Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression.

The T helper type 2 (Th2) cytokine genes Il4 , Il5 , and Il13 are contained within a 140-kb region of mouse chromosome 11 and their expression is controlled by a locus control region (LCR) embedded within this locus. The LCR is composed of a number of DNase I–hypersensitive sites (HSs), which are be... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America April 23, 2013, Vol.110(17), pp.6955-6960
Main Author: Williams, Adam
Other Authors: Lee, Gap Ryol , Spilianakis, Charalampos G , Hwang, Soo Seok , Eisenbarth, Stephanie C , Flavell, Richard A
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1304720110
Link: http://search.proquest.com/docview/1346117707/?pq-origsite=primo
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recordid: proquest1346117707
title: Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression.
format: Article
creator:
  • Williams, Adam
  • Lee, Gap Ryol
  • Spilianakis, Charalampos G
  • Hwang, Soo Seok
  • Eisenbarth, Stephanie C
  • Flavell, Richard A
subjects:
  • ATP-Binding Cassette Transporters–Metabolism
  • Analysis of Variance–Genetics
  • Animals–Metabolism
  • Blotting, Western–Genetics
  • Chromatin Immunoprecipitation–Metabolism
  • Cytokines–Genetics
  • DNA Primers–Immunology
  • Deoxyribonuclease I–Genetics
  • Enzyme-Linked Immunosorbent Assay–Genetics
  • Flow Cytometry–Administration & Dosage
  • Gene Expression Regulation–Immunology
  • Locus Control Region–Immunology
  • Mice–Immunology
  • Mice, Knockout–Immunology
  • Mutation–Immunology
  • Ovalbumin–Immunology
  • Real-Time Polymerase Chain Reaction–Immunology
  • Th2 Cells–Immunology
  • ATP-Binding Cassette Transporters
ispartof: Proceedings of the National Academy of Sciences of the United States of America, April 23, 2013, Vol.110(17), pp.6955-6960
description: The T helper type 2 (Th2) cytokine genes Il4 , Il5 , and Il13 are contained within a 140-kb region of mouse chromosome 11 and their expression is controlled by a locus control region (LCR) embedded within this locus. The LCR is composed of a number of DNase I–hypersensitive sites (HSs), which are believed to encompass the regulatory core of the LCR. To determine the function of these sites, mutant mice were generated in which combinations of these HSs had been deleted from the endogenous LCR, and the effect on Th2 cytokine expression was assessed through the use of in vivo and in vitro models. These experiments revealed that, although all of the hypersensitive sites analyzed are important for appropriate LCR function, some sites are more important than others in regulating cytokine expression. Interestingly, each LCR mutation showed contrasting effects on cytokine expression, in some cases with mutants displaying opposing phenotypes between in vitro cultures and in vivo immunizations. These studies indicated that Rad50 hypersensitive site 6 was the singularly most important HS for Th2 cytokine expression, displaying consistent reductions in cytokine levels in all models tested. Furthermore analysis of chromatin modifications revealed that deletion of Rad50 hypersensitive site 6 impacted epigenetic modifications at the promoters of the Il4 , Il5 , and Il13 genes as well as other regulatory sites within the Th2 locus.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1304720110
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleHypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression.
creatorWilliams, Adam ; Lee, Gap Ryol ; Spilianakis, Charalampos G ; Hwang, Soo Seok ; Eisenbarth, Stephanie C ; Flavell, Richard A
contributorWilliams, Adam (correspondence author) ; Williams, Adam (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, April 23, 2013, Vol.110(17), pp.6955-6960
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1304720110
subjectATP-Binding Cassette Transporters–Metabolism ; Analysis of Variance–Genetics ; Animals–Metabolism ; Blotting, Western–Genetics ; Chromatin Immunoprecipitation–Metabolism ; Cytokines–Genetics ; DNA Primers–Immunology ; Deoxyribonuclease I–Genetics ; Enzyme-Linked Immunosorbent Assay–Genetics ; Flow Cytometry–Administration & Dosage ; Gene Expression Regulation–Immunology ; Locus Control Region–Immunology ; Mice–Immunology ; Mice, Knockout–Immunology ; Mutation–Immunology ; Ovalbumin–Immunology ; Real-Time Polymerase Chain Reaction–Immunology ; Th2 Cells–Immunology ; ATP-Binding Cassette Transporters
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descriptionThe T helper type 2 (Th2) cytokine genes Il4 , Il5 , and Il13 are contained within a 140-kb region of mouse chromosome 11 and their expression is controlled by a locus control region (LCR) embedded within this locus. The LCR is composed of a number of DNase I–hypersensitive sites (HSs), which are believed to encompass the regulatory core of the LCR. To determine the function of these sites, mutant mice were generated in which combinations of these HSs had been deleted from the endogenous LCR, and the effect on Th2 cytokine expression was assessed through the use of in vivo and in vitro models. These experiments revealed that, although all of the hypersensitive sites analyzed are important for appropriate LCR function, some sites are more important than others in regulating cytokine expression. Interestingly, each LCR mutation showed contrasting effects on cytokine expression, in some cases with mutants displaying opposing phenotypes between in vitro cultures and in vivo immunizations. These studies indicated that Rad50 hypersensitive site 6 was the singularly most important HS for Th2 cytokine expression, displaying consistent reductions in cytokine levels in all models tested. Furthermore analysis of chromatin modifications revealed that deletion of Rad50 hypersensitive site 6 impacted epigenetic modifications at the promoters of the Il4 , Il5 , and Il13 genes as well as other regulatory sites within the Th2 locus.
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titleHypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression.
authorWilliams, Adam ; Lee, Gap Ryol ; Spilianakis, Charalampos G ; Hwang, Soo Seok ; Eisenbarth, Stephanie C ; Flavell, Richard A
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