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Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches

Czimmerer, Zsolt and Horváth, Attila and Dániel, Bence and Nagy, Gergely and Cuaranta-Monroy, Ixchelt and Kiss, Máté and Kolostyák, Zsuzsanna and Póliska, Szilárd and Steiner, László and Giannakis, Nikolas and Varga, Tamás and Nagy, László (2018) Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1861 (1). pp. 14-28. ISSN 0006-3002

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Abstract

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 NFkappaB-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.

Item Type: Article
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH426 Genetics / genetika, örökléstan
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 19 Mar 2019 10:41
Last Modified: 19 Mar 2019 10:41
URI: http://real.mtak.hu/id/eprint/92146

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