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

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 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.

Long noncoding RNAs in autoimmune diseases

“…ncRNAs are grouped into two major classes according to their size: small ncRNAs (<200 nucleotides) and long ncRNAs (≥200 nucleotides). MicroRNAs (miRNAs; 19–22 nucleotides) have been proven to regulate the expression of many genes and signaling pathways in autoimmune diseases, such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and multiple sclerosis (MS) …”

“…MicroRNAs (miRNAs; 19-22 nucleotides) have been proven to regulate the expression of many genes and signaling pathways in autoimmune diseases, such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and multiple sclerosis (MS). [4][5][6] The other major type of ncRNA, lncRNAs, has recently received extensive attention due to their potential functions. lncRNAs are non-protein-coding RNA transcripts longer than 200 nucleotides that can interact with proteins, DNA, and RNA.…”

The Significance of Regulatory MicroRNAs: Their Roles in Toxicodynamics of Mycotoxins and in the Protection Offered by Dietary Therapeutics Against Mycotoxin‐Induced Toxicity

“…() reported that miR‐21 was an important contributor for promoting vascular inflammation, and the loss of miR‐21 would result in less inflammatory phenotype and help attenuate stent‐induced inflammatory vascular disease. MiR‐130a, miR‐132‐3p, let‐7b, miR‐155, miR‐146a, let‐7d‐5p, miR‐221, miR‐222, and miR‐144 have also been associated with inflammatory gene regulation, and certain human health problems and diseases such as metabolic syndrome, epilepsy, brain injury of intracerebral hemorrhage (Czimmerer et al., ; Marques‐Rocha et al., ; Srivastava, Dixit, Banerjee, Tripathi, & Sarat Chandra, ; Yu et al., ). MiR‐130a, miR‐132, miR‐155, and miR‐221 are found to be able to regulate the toxicity of mycotoxins (Croston, Lemons, Beezhold, & Green, ; Qi et al., ; Valencia‐Quintana et al., ).…”

DNA loop organization in dorsal root ganglion neurons: effects of peripheral inflammation

“…Under peripheral inflammation, DRG neurons are stimulated by inflammatory mediators, which sensitize neurons for pain perception by altering the expression of many genes [12][13][14][15][16]. Since changes in the expression of some genes during inflammation are associated with chromatin reorganization [17], it was interesting to assess the extent of such reorganization in DRG neurons caused by inflammation.…”