Inflammatory Immune-Associated eRNA: Mechanisms, Functions and Therapeutic Prospects

Abstract

The rapid development of multiple high-throughput sequencing technologies has made it possible to explore the critical roles and mechanisms of functional enhancers and enhancer RNAs (eRNAs). The inflammatory immune response, as a fundamental pathological process in infectious diseases, cancers and immune disorders, coordinates the balance between the internal and external environment of the organism. It has been shown that both active enhancers and intranuclear eRNAs are preferentially expressed over inflammation-related genes in response to inflammatory stimuli, suggesting that enhancer transcription events and their products influence the expression and function of inflammatory genes. Therefore, in this review, we summarize and discuss the relevant inflammatory roles and regulatory mechanisms of eRNAs in inflammatory immune cells, non-inflammatory immune cells, inflammatory immune diseases and tumors, and explore the potential therapeutic effects of enhancer inhibitors affecting eRNA production for diseases with inflammatory immune responses.

Keywords: cancers; eRNA; enhancer transcription events; immune inflammatory; therapeutic prospects.

Figure 1

Activation mechanism of enhancers and super enhancer. (A) Enhancer activation. Multifactorial stimulation causes pTFs binding to nucleosomes leading to ChR and further recruitment of LDTFs, cTFs and CoFs that assist enhancer activation and histone methylation. On this basis, HAT, GTFs and RNAPII are recruited and ultimately contribute to enhancer transcription bi-directionally. In addition, DME are recruited to regulate DNA methylation and p300 status at the initial stage of enhancer activation. (B) Super enhancers are large clusters of enhancers with high levels of cell-specific transcription factors and cofactors that can ultimately express higher levels of eRNAs.

Figure 2

The inflammatory immune role of eRNAs in cells and diseases. eRNAs have a significant contribution in inflammatory immune cells, non-inflammatory immune cells, inflammatory immune diseases and tumor inflammatory alterations.

Figure 3

Mechanism of enhancer transcription and eRNAs to regulate target genes. (A) Following enhancer activation, GTFs and serine 5-phosphorylated form of RNAPII (Ser5p) are recruited, which leads CBC to binding to eRNA via m7G, ultimately initiating enhancer transcription. During the enhancer elongation, Ser2p is hypoenriched. pTEFb, BRD4 and the eRNAs being transcribed all affect transcription elongation. Subsequently, the nascent eRNAs interacts with RNAPII CTD to terminate transcription. In addition, the integrator, WDR82 and Tyr1p assist in correct enhancer transcription termination. Finally, the NEXT complex mediates the degradation of eRNAs. (B) Chromatin loops are generated under the influence of LDTFs, histone methylation or acetylation, cohesin-CTCF complex and interphase chromosome topologically associated domain, and ultimately activate target gene transcription. (C) Specific mechanisms have been demonstrated for eRNAs to affect enhancer activity, E-P loop formation, and transcription of downstream target genes.

Figure 4

Schematic representation of putative therapeutic targets to enhancer transcription events and eRNA landscapes. CDKI, cyclin-dependent kinase inhibitors; HATI, histone acetyltransferase inhibitors; HDACI, histone deacetylase inhibitors; LSD1, lysine-specific demethylase 1; JAKI, janus kinase inhibitors; TFM, transcription factors inhibitors; CI, co-repressors inhibitors.