Epitranscriptomics and Epigenetics in Multi-layered Regulation of Innate Immunity

Multicellular organisms are continuously exposed to viruses, bacteria and yeast or fungus. In response, they have developed intricate, multilayered defense systems, with innate immunity as a key component. This evolutionarily conserved mechanism provides a rapid, specific (animals) or non-specific (plants) response.

In animals, including humans, innate immunity involves physical barriers (skin, mucosa), immune cells (macrophages, neutrophils), and molecular effectors (cytokines and antimicrobial peptides). These elements detect pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), and Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). The initial recognition of pathogens triggers primary responses that shift gene expression profiles. Induced genes included those encoding IFNs and cytokines. These factors amplify signals through cell-surface receptors via autocrine and paracrine mechanisms to elicit secondary signals.

On the contrary to animals, plants, despite lacking immune cells, possess a sophisticated non-specific innate immune system structured into two layers: pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI is initiated by membrane-localized PRRs detecting conserved microbial features, while ETI is activated by intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) recognizing pathogen effectors. These immune responses activate defense gene expression, reinforce the cell wall, generate reactive oxygen species (ROS), and may induce localized cell death.

Epitranscriptomics and epigenetics add complex regulatory dimensions in animals or plants, RNA methylation (N6-methyl-adenosine, m6A), DNA methylation, histone modifications, chromatin remodeling to fine-tune immune responses. Recent studies demonstrate that m6A modification tightly controls various innate immune responses such as the expression of interferons (IFNs), inflammatory responses, and macrophages and dendritic cells homeostasis. m6A can either improve the immune response against pathogens and viruses or tame the immune response to prevent aggressive immunopathological damage by modulating the mRNA life cycle transcriptionally and post-transcriptionally, which include pre-mRNA processing, export, translation and decay processes. Similarly, histone modifications or DNA methylation modulate transcription of inflammatory genes. For instance, histone acetylation in humans promotes inflammatory gene transcription, while DNA methylation can silence them to prevent autoimmunity. In plants, active histone marks like H3K4me3 and H3K9ac upregulate defense genes, whereas repressive marks like H3K27me3 suppress immune activation when not needed.

The interplay between epitranscriptomics and epigenetic layers provides organisms to respond swiftly to challenges while avoiding excessive or misdirected immune activation. In summary, the regulation of innate immunity and defense mechanisms is a multifaceted process involving m6A modification of genes and epigenetic modifications. Understanding these multilayered regulatory networks across diverse taxa, from plants to humans, not only deepens our knowledge of evolutionary immunity but also opens new avenues for improving disease resistance in crops and developing immunotherapies in medicine.

In this Research Topic, we are looking to compile recent advanced research in Epitranscriptomics and epigenetics area to understand the unexplored gene expression mechanisms at transcription or post transcription level. We invite all research groups around the world to submit their original research articles, review articles, short communication, break-through research or commentaries. We also inviting the innovative opinions to enrich our readers to understand the importance and future directions of this emerging area of research.

We encourage researchers to embrace this new area of epitranscriptomics in anticipation that more extensive research on m6A or epigenetics in immune cells and the immune response will open the door for exploiting immune cells to develop novel therapeutic strategies including cancer immunotherapy, antiviral, anti-inflammatory and autoimmune disease therapies.