title: The transcriptional regulator network of human inflammatory macrophages is defined by open chromatin.
abstract: Differentiation of inflammatory macrophages from monocytes is characterized by an orderly integration of epigenetic and transcriptional regulatory mechanisms guided by lineage-determining transcription factors such as PU.1. Further activation of macrophages leads to a stimulus- or microenvironment-specific signal integration with subsequent transcriptional control established by the action of tissue- or signal-associated transcription factors. Here, we assess four histone modifications during human macrophage activation and integrate this information with the gene expression data from 28 different macrophage activation conditions in combination with GM-CSF. Bioinformatically, for inflammatory macrophages we define a unique network of transcriptional and epigenetic regulators (TRs), which was characterized by accessible promoters independent of the activation signal. In contrast to the general accessibility of promoters of TRs, mRNA expression of central TRs belonging to the TR network displayed stimulus-specific expression patterns, indicating a second level of transcriptional regulation beyond epigenetic chromatin changes. In contrast, stringent integration of epigenetic and transcriptional regulation was observed in networks of TRs established from somatic tissues and tissue macrophages. In these networks, clusters of TRs with permissive histone marks were associated with high gene expression whereas clusters with repressive chromatin marks were associated with absent gene expression. Collectively, these results support that macrophage activation during inflammation in contrast to lineage determination is mainly regulated transcriptionally by a pre-defined TR network.
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Susanne V
authors.initials: SV
authors.lastname: Schmidt
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krebs
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Jia
authors.initials: J
authors.lastname: Xue
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Baßler
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Günther
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Hardt
authors.affiliation: Schultze Know How Beteiligungsgesellschaft mbH, Kirschblütenweg 2, 53639 Königswinter, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schultze
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Jil
authors.initials: J
authors.lastname: Sander
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klee
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Theis
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kraut
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.|German Center for Neurodegenerative Diseases, 53175 Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D002843:Chromatin; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor