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NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers

The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America 14 January 2014, Vol.111(2), pp.705-10
Main Author: Wang, Hongfang
Other Authors: Zang, Chongzhi , Taing, Len , Arnett, Kelly L , Wong, Yinling Joey , Pear, Warren S , Blacklow, Stephen C , Liu, X Shirley , Aster, Jon C
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; PMID: 24374627 Version:1 ; DOI: 10.1073/pnas.1315023111
Link: http://pubmed.gov/24374627
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recordid: medline24374627
title: NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
format: Article
creator:
  • Wang, Hongfang
  • Zang, Chongzhi
  • Taing, Len
  • Arnett, Kelly L
  • Wong, Yinling Joey
  • Pear, Warren S
  • Blacklow, Stephen C
  • Liu, X Shirley
  • Aster, Jon C
subjects:
  • Notch Signaling
  • Gene Regulation
  • Enhancer Elements, Genetic -- Genetics
  • Gene Expression Regulation -- Physiology
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein -- Metabolism
  • Multiprotein Complexes -- Metabolism
  • Receptor, Notch1 -- Metabolism
  • Signal Transduction -- Physiology
ispartof: Proceedings of the National Academy of Sciences of the United States of America, 14 January 2014, Vol.111(2), pp.705-10
description: The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic...
language: eng
source:
identifier: E-ISSN: 1091-6490 ; PMID: 24374627 Version:1 ; DOI: 10.1073/pnas.1315023111
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleNOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
creatorWang, Hongfang ; Zang, Chongzhi ; Taing, Len ; Arnett, Kelly L ; Wong, Yinling Joey ; Pear, Warren S ; Blacklow, Stephen C ; Liu, X Shirley ; Aster, Jon C
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subjectNotch Signaling ; Gene Regulation ; Enhancer Elements, Genetic -- Genetics ; Gene Expression Regulation -- Physiology ; Immunoglobulin J Recombination Signal Sequence-Binding Protein -- Metabolism ; Multiprotein Complexes -- Metabolism ; Receptor, Notch1 -- Metabolism ; Signal Transduction -- Physiology
descriptionThe main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic...
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titleNOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
descriptionThe main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic...
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abstractThe main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic...
doi10.1073/pnas.1315023111
pmid24374627
date2014-01-14