title: Redefining the transcriptional regulatory dynamics of classically and alternatively activated macrophages by deepCAGE transcriptomics.
abstract: Classically or alternatively activated macrophages (M1 and M2, respectively) play distinct and important roles for microbiocidal activity, regulation of inflammation and tissue homeostasis. Despite this, their transcriptional regulatory dynamics are poorly understood. Using promoter-level expression profiling by non-biased deepCAGE we have studied the transcriptional dynamics of classically and alternatively activated macrophages. Transcription factor (TF) binding motif activity analysis revealed four motifs, NFKB1_REL_RELA, IRF1,2, IRF7 and TBP that are commonly activated but have distinct activity dynamics in M1 and M2 activation. We observe matching changes in the expression profiles of the corresponding TFs and show that only a restricted set of TFs change expression. There is an overall drastic and transient up-regulation in M1 and a weaker and more sustainable up-regulation in M2. Novel TFs, such as Thap6, Maff, (M1) and Hivep1, Nfil3, Prdm1, (M2) among others, were suggested to be involved in the activation processes. Additionally, 52 (M1) and 67 (M2) novel differentially expressed genes and, for the first time, several differentially expressed long non-coding RNA (lncRNA) transcriptome markers were identified. In conclusion, the finding of novel motifs, TFs and protein-coding and lncRNA genes is an important step forward to fully understand the transcriptional machinery of macrophage activation.
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Sugata
authors.initials: S
authors.lastname: Roy
authors.affiliation: Massey University, Institute of Natural and Mathematical Sciences, Auckland, New Zealand.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmeier
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia.
authors.forename: Tanvir
authors.initials: T
authors.lastname: Alam
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa.
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa.
authors.forename: Mumin
authors.initials: M
authors.lastname: Ozturk
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa.
authors.forename: Ousman
authors.initials: O
authors.lastname: Tamgue
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Preventive Medicine and Diagnosis Innovation Program (PMI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Michiel J L
authors.initials: MJ
authors.lastname: de Hoon
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Preventive Medicine and Diagnosis Innovation Program (PMI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Preventive Medicine and Diagnosis Innovation Program (PMI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Alistair R R
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa.
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Massey University, Institute of Natural and Mathematical Sciences, Auckland, New Zealand King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa Riken Preventive Medicine and Diagnosis Innovation Program (PMI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa University of Cape Town, Health Science Faculty, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Cape Town, South Africa harukazu@gsc.riken.jp.
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan Riken Omics Science Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan harukazu@gsc.riken.jp.
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D007371:Interferon-gamma / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D018793:Interleukin-13; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA