Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches
| Autor: | Mate Kiss, Attila Horvath, Tamas Varga, Zsolt Czimmerer, Ixchelt Cuaranta-Monroy, Gergely Nagy, Laszlo Nagy, Nikolas Giannakis, Zsuzsanna Kolostyak, László Steiner, Szilárd Póliska, Bence Daniel |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Transcription Genetic Biophysics Gene regulatory network Computational biology Regulatory Sequences Nucleic Acid Biology Biochemistry Mice 03 medical and health sciences Structural Biology Genetics Transcriptional regulation Animals Humans Gene Regulatory Networks Epigenetics Elméleti orvostudományok Promoter Regions Genetic Enhancer Molecular Biology Transcription factor Inflammation Regulation of gene expression Transcription Factor RelA High-Throughput Nucleotide Sequencing Promoter Orvostudományok Chromatin MicroRNAs 030104 developmental biology Gene Expression Regulation |
| Zdroj: | Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms |
| Popis: | MicroRNAs are important components of the post-transcriptional fine-tuning of macrophage gene expression in physiological and pathological conditions. However, the mechanistic underpinnings and the cis-acting genomic factors of how macrophage polarizing signals induce miRNA expression changes are not well characterized. Therefore, we systematically evaluated the transcriptional basis underlying the inflammation-mediated regulation of macrophage microRNome using the combination of different next generation sequencing datasets. We investigated the LPS-induced expression changes at mature miRNA and pri-miRNA levels in mouse macrophages utilizing a small RNA-seq method and publicly available GRO-seq dataset, respectively. Next, we identified an enhancer set associated with LPS-responsive pri-miRNAs based on publicly available H3K4 mono-methylation-specific ChIP-seq and GRO-seq datasets. This enhancer set was further characterized by the combination of publicly available ChIP and ATAC-seq datasets. Finally, direct interactions between the miR-155-coding genomic region and its distal regulatory elements were identified using a 3C-seq approach. Our analysis revealed 15 robustly LPS-regulated miRNAs at the transcriptional level. In addition, we found that these miRNA genes are associated with an inflammation-responsive enhancer network. Based on NFκB-p65 and JunB transcription factor binding, we showed two distinct enhancer subsets associated with LPS-activated miRNAs that possess distinct epigenetic characteristics and LPS-responsiveness. Finally, our 3C-seq analysis revealed the LPS-induced extensive reorganization of the pri-miR-155-associated functional chromatin domain as well as chromatin loop formation between LPS-responsive enhancers and the promoter region. Our genomic approach successfully combines various genome-wide datasets and allows the identification of the putative regulatory elements controlling miRNA expression in classically activated macrophages. |
| Databáze: | OpenAIRE |
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