Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages

Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become...

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Vydáno v:Immunity (Cambridge, Mass.) Ročník 32; číslo 3; s. 317
Hlavní autoři: Ghisletti, Serena, Barozzi, Iros, Mietton, Flore, Polletti, Sara, De Santa, Francesca, Venturini, Elisa, Gregory, Lorna, Lonie, Lorne, Chew, Adeline, Wei, Chia-Lin, Ragoussis, Jiannis, Natoli, Gioacchino
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 26.03.2010
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ISSN:1097-4180, 1097-4180
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Abstract Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.
AbstractList Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.
Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the acetyl-transferase p300, which has allowed genome-wide enhancer identification. However, the regulatory principles by which subsets of enhancers become active in specific developmental and/or environmental contexts are unknown. We exploited inducible p300 binding to chromatin to identify, and then mechanistically dissect, enhancers controlling endotoxin-stimulated gene expression in macrophages. In these enhancers, binding sites for the lineage-restricted and constitutive Ets protein PU.1 coexisted with those for ubiquitous stress-inducible transcription factors such as NF-kappaB, IRF, and AP-1. PU.1 was required for maintaining H3K4me1 at macrophage-specific enhancers. Reciprocally, ectopic expression of PU.1 reactivated these enhancers in fibroblasts. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors determines the activity of a distinct group of enhancers. We suggest that this may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.
Author Barozzi, Iros
Gregory, Lorna
Chew, Adeline
Ghisletti, Serena
De Santa, Francesca
Lonie, Lorne
Wei, Chia-Lin
Mietton, Flore
Polletti, Sara
Ragoussis, Jiannis
Venturini, Elisa
Natoli, Gioacchino
Author_xml – sequence: 1
  givenname: Serena
  surname: Ghisletti
  fullname: Ghisletti, Serena
  organization: Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan, Italy
– sequence: 2
  givenname: Iros
  surname: Barozzi
  fullname: Barozzi, Iros
– sequence: 3
  givenname: Flore
  surname: Mietton
  fullname: Mietton, Flore
– sequence: 4
  givenname: Sara
  surname: Polletti
  fullname: Polletti, Sara
– sequence: 5
  givenname: Francesca
  surname: De Santa
  fullname: De Santa, Francesca
– sequence: 6
  givenname: Elisa
  surname: Venturini
  fullname: Venturini, Elisa
– sequence: 7
  givenname: Lorna
  surname: Gregory
  fullname: Gregory, Lorna
– sequence: 8
  givenname: Lorne
  surname: Lonie
  fullname: Lonie, Lorne
– sequence: 9
  givenname: Adeline
  surname: Chew
  fullname: Chew, Adeline
– sequence: 10
  givenname: Chia-Lin
  surname: Wei
  fullname: Wei, Chia-Lin
– sequence: 11
  givenname: Jiannis
  surname: Ragoussis
  fullname: Ragoussis, Jiannis
– sequence: 12
  givenname: Gioacchino
  surname: Natoli
  fullname: Natoli, Gioacchino
BackLink https://www.ncbi.nlm.nih.gov/pubmed/20206554$$D View this record in MEDLINE/PubMed
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Snippet Enhancers determine tissue-specific gene expression programs. Enhancers are marked by high histone H3 lysine 4 mono-methylation (H3K4me1) and by the...
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SubjectTerms Animals
Binding Sites
Cells, Cultured
Chromatin - immunology
Chromatin - metabolism
E1A-Associated p300 Protein - genetics
E1A-Associated p300 Protein - metabolism
Female
Gene Expression Profiling
Gene Expression Regulation
Inflammation - genetics
Inflammation - immunology
Inflammation - metabolism
Lipopolysaccharides - immunology
Macrophages - immunology
Macrophages - metabolism
Mice
Protein Binding
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Regulatory Sequences, Nucleic Acid
Trans-Activators - genetics
Trans-Activators - metabolism
Title Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages
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