This Research Topic deepens a better understanding of epigenetics in immune component of inflammation and highlights the clinical significance of epigenetic regulation in disease diagnosis and drug discovery. This Research Topic accepted a total of 42 articles from 285 authors, demonstrating great interests in this field. This topic can be roughly divided into the following subtopics:
The hypermethylation in the promoter regions of inflammatory genes often leads to their inactivation and suppresses inflammatory diseases. Conversely, the hypomethylation in the cis-acting elements of these genes upregulates their levels and contributes to inflammation . In this special issue, Bordagaray et al. found the promoter of TLR2 gene in peripheric mononuclear blood cells (PBMCs) from patients with apical periodontitis (AP) has much higher global methylation than that of controls, suggesting that hypermethylation is responsible for sustained systemic inflammation in AP. Zhao et al summarized the roles of DNA methylation of T cell related genes in the development and differentiation of T lymphocytes, and the predications of diagnosis and drug efficacy. Chen's group determined the molecular signatures associated with meningitis induced by Glaesserella parasuis based on methylome and transcriptome-based integration analysis, which provides potential diagnosis biomarker and therapeutic targets for G. parasuis induced pig meningitis. DNA methylation also contributes to inflammation induced tumorigenesis . Yang and Huang et al summarized the emerging roles of DNA methylation-mediated inflammation in tumorigenesis of non-small cell lung cancer (NSCL) and reckoned that targeting these cell events is a potent strategy for NSCL treatment. Chen Nian et al also considered that the DNA methylation regulation of inflammation is the key factor for tumor microenvironment (TME) in glioblastoma. Based on DNA methylation-driven genes based prognostic model, Tian et al identified 5 target genes and 5 agents with therapeutic potentials for high-risk breast cancer (BC) patients. Further in vitro analysis indicated that (+)-JQ1 is the best candidate agent for BC treatment among them. Yang and He et al identified and characterized extrachromosomal circular DNAs (eccDNAs/ecDNAs) in placentas with fetal growth restriction (FGR) based on circle-seq and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and shed light on the formation mechanisms and the networks with noncoding RNAs (ncRNAs), which provided a new vision for the screening of new biomarkers and therapeutic targets for FGR. N6-methyladenosine (m6A) was a common RNA modification mediating inflammation-related diseases via regulating genetic expression at the post-transcriptional level . Guo and Wang et al. comprehensively evaluated the correlation between N6-methyladenosine (m6A) regulators and immune microenvironment in pancreatic cancer (PC) via integrating analysis of 7 PC databases, and found that these samples can be divided into two clusters by consensus clustering for m6A regulators. The results showed that patients with lower m6A regulators tended to higher immune cell infiltration and a better survival. Further study found that 6 m6A regulators could be used as a prognostic signature to assess sensitization to immune checkpoint inhibitor and overall survival (OS) of PC patients, and patient low-risk score is apt to with higher response to immunotherapy and a longer OS. Du et al also found similar functions of m6A regulators in acute myeloid leukemia. Apart from coding RNAs, m6A also could modify ncRNAs and regulate inflammation . Hu et al found that m6A modified cirRNA promoted the injury of MAC-T cells infected by Staphylococcus aureus and Escherichia coli via CircRNA-miRNA-mRNA interaction networks, suggesting m6A-modified CircRNA is a potential target for mastitis and other inflammatory diseases. Wu et al. comprehensively analyzed the correlations among the expression of m6A-related LncRNA, TME, and OS of osteosarcoma, the results showed that m6A-related long ncRNAs (lncRNAs) is positively correlated with occurrence and mediates TME remodeling in osteosarcoma via infiltrating immune cells, indicating m6A-related lncRNAs can be used as a biomarker to predict patient prognosis and target cancer therapy.
NcRNAs including microRNAs and lncRNAs are another kinds of epigenetic modes, which could also regulate various inflammatory events . Rodrí guez-Muguruza et al found that a panel of exomiR-25-3p, exomiR-0451a, and soluble TWEAK could be used as biomarker for early diagnosis of RA. Wang and Jia et al verified that miR-382 promoted M2-like macrophage (Mф) polarization via activating SIRP-α/STAT3 signaling in aristolochic acid-induced renal fibrosis, suggesting that miR-382 is a critical regulator for M2-like Mф polarization and a promising therapeutic target for renal fibrosis. Peng et al reviewed the biosynthesis and functions of miR-233 in innate immunity, summarized the roles of miR-233 in liver physiopathology and prospected the therapeutic strategies. Jiang and Xu et al outlined the roles of miRNAs-mediated inflammation in wound healing and considered that miRNAs are potential therapeutic target for wound healing. Luo et al explored the mechanisms regulating dysfunctions of immune cells and inflammatory phenotypes in ulcerative colitis (UC) based on several bioinformational analysis, and identified XIST, miR-9-5p, miR-129-5p, and miR-340-5p are the potential therapeutic targets for UC. Gong et al performed the small RNAs and miRNAs profiling and integrative analysis of chronic epididymitis (CE) and identified a regulatory network containing 22 miRNAs and 31genes, which would contribute to deepening the understand of roles of miRNA-mRNA in the pathogenesis of CE and providing molecular candidates for the development of potential biomarkers for human CE. LncRNA, an emerging epigenetic modification, has been found to mediate varieties of inflammatory diseases . Jiang and Li et al showed that LncRNAs could modulate the Mф polarization though pro-inflammatory or antiinflammatory mechanisms and thus mediate the process of inflammatory diseases such as infection, cancer, autoimmune diseases, and metabolic diseases. Guo and Xie et al outlined the TEM-regulated functions of LncRNAs via mediating Mф polarization, neutrophil recruitment, T cells functions, and NK cells cytotoxicity, and contributed to tumorigenesis, angiogenesis, and cancer metastasis. Moreover, they also summarized and prospected the prospective of LncRNAs as cancer prognostic biomarkers and therapeutic targets in clinic.
Post-translational modifications such as methylation/demethylation, acetylation, O-GlcNAcylation, and phosphorylation are epigenetic modes accurately orchestrating the activation or inactivation of inflammation . Lin et al summarized the various roles of histone modifications in inflammatory diseases, which provided the potential diagnosed biomarker and therapeutic target for these diseases. While Wen et al introduced the roles of phosphorylation in modulating inflammatory cell death, which suggested some kinases or phosphatases mediated inflammatory diseases are potential target for inflammation-related diseases. Ouyang et al summarized the effects of O-GlcNAcylation on tumor-associated inflammation and the mechanisms of O-GlcNAc-mediated inflammation in tumorigenesis, which provides a theoretical basis for the development of anti-cancer agents against inflammatory tumors via targeting O-GlcNAcylation. Chronic inflammation triggered methylation/demethylation switch is involved in tumor initiation and progression [25,26]. Li and Song et al found that EZH2 inhibitors GSK126 and EPZ6438 exhibited their anticancer activities in colorectal cancer (CRC) via directly suppressing proliferation of CRC cells, and promoting transformation of Mф polarization to tumor-suppressive M1 Mф. Yang and Hu et al summarized the roles of JMJD histone demethylases in the crosstalk between inflammation and cancer and highlighted the potential applications of modulating cancer-related inflammation via targeting JMJD histone demethylases for cancer therapy. Wang and Yang et al focused on the structure, biological function and potential application of JMJD6 in tumor immune regulation and targeted therapy. Acetylation is also an important epigenetic modification involved in multiple inflammatory diseases . Zhu et al demonstrated that histone deacetylase 3 (HDAC3) activated NF-κB signaling via p65 deacetylation and promoted local prostaglandin E2 (PGE2) production in activated-microglia from damaged cortex. HDAC3-mediated PGE2 production by microglia promoted phobic anxiety susceptibility after stroke, suggesting targeting HDAC3 might be a candidate new therapy. Bromodomain and extra-terminal domain (BET) proteins were found to mediate lots of inflammatory diseases [6,7]. Our studies found that acetylation reader BRD4 inhibitor 13a could eliminate NF-κBdriven triple-negative breast cancer (TNBC) cells via blocking the interaction BRD4 and acetylated RelA at lysine-310 site . Lei et al revealed that BRD4 also modulated Histone 3 acetylation via FGFR2-BRD4 axis, and BRD4 inhibitors exhibited synergistic effect with immune check blockade in TNBC therapy. O'Connor et al demonstrated that BET inhibitor (+)-JQ1-treatment reduced LPSinduced chromatin remodeling and suppressed the expression of inflammatory genes in Mф, and alleviated microbiota-dependent colitis compared with vehicle-treated mice.
In a word, this Research Topic summed up recent progress on the pivotal roles of epigenetics in immune component of inflammation and their contributions to inflammatory diseases, which provides new insight into prognostic biomarkers, and promising diagnostic and therapeutic strategies for inflammatory diseases.