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.
Highlights
Macrophages can be phenotypically polarized by the microenvironment to activate specific functional programs that are broadly classified into two main groups, classically activated macrophages (M1) and alternatively activated macrophages (M2)(1,2)
As a satellite study within the FANTOM5 phase 2 activity, which defined the dynamics of enhancer and promoter activity during mammalian cellular activation and differentiation [37], we focused on the analysis of transcriptional regulation and marker genes, as well as transcribed long non-coding RNAs during classical and alternative activation in murine primary macrophages
Considering that 3,361 promoters for 953 Transcription factor (TF) genes were expressed in bone marrow-derived macrophages (BMDMs) at time 0 h, the results showed that only a restricted number of TF genes change on a gene expression for both polarization events
Summary
Macrophages can be phenotypically polarized by the microenvironment to activate specific functional programs that are broadly classified into two main groups, classically activated macrophages (M1) and alternatively activated macrophages (M2)(1,2). Promoter-based gene expression analysis allowed us to identify new transcription marker genes and lncRNA genes in IFN␥ - and IL-4/IL-13-stimulated macrophages.
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