Sexual dimorphism of miRNA expression: a new perspective in understanding the sex bias of autoimmune diseases

Abstract

Autoimmune diseases encompass a diverse group of diseases which emanate from a dysregulated immune system that launches a damaging attack on its own tissues. Autoimmune attacks on self tissues can occur in any organ or body system. A notable feature of autoimmune disease is that a majority of these disorders occur predominantly in females. The precise basis of sex bias in autoimmune diseases is complex and potentially involves sex chromosomes, sex hormones, and sex-specific gene regulation in response to internal and external stimuli. Epigenetic regulation of genes, especially by microRNAs (miRNAs), is now attracting significant attention. miRNAs are small, non-protein-coding RNAs that are predicted to regulate a majority of human genes, including those involved in immune regulation. Therefore, it is not surprising that dysregulated miRNAs are evident in many diseases, including autoimmune diseases. Because there are marked sex differences in the incidence of autoimmune diseases, this review focuses on the role of sex factors on miRNA expression in the context of autoimmune diseases, an aspect not addressed thus far. Here, we initially review miRNA biogenesis and miRNA regulation of immunity and autoimmunity. We then summarize the recent findings of sexual dimorphism of miRNA expression in diverse tissues, which imply a critical role of miRNA in sex differentiation and in sex-specific regulation of tissue development and/or function. We also discuss the important contribution of the X chromosome and sex hormones to the sexual dimorphism of miRNA expression. Understanding sexually dimorphic miRNA expression in sex-biased autoimmune diseases not only offers us new insight into the mechanism of sex bias of the disease but will also aid us in developing new sex-based therapeutic strategies for the efficient treatment of these diseases with a sex bias.

Keywords: X chromosome; autoimmune diseases; immune regulation; microRNA; sex differences; sex hormones.

Figure 1

microRNA (miRNA) biogenesis. Notes: The miRNA gene is transcribed by RNA polymerase II and III into primary miRNA (pri-miRNA). Classically, the pri-miRNA is cleaved by Drosha (a) in the nucleus to generate precursor miRNA (pre-miRNA). Biogenesis of nonclassical miRNA, mirtron (b), bypasses Drosha processing to form pre-miRNA through splicing out from the pri-miRNA. The pre-miRNA is exported to the cytoplasm by Exportin-5. In the cytoplasm, the pre-miRNA is further processed by Dicer to yield ~22 nts long, imperfectly matched miRNA/miRNA* duplex. This duplex is loaded into Argonaute (Ago) protein to generate effector complex, RNA-induced silencing complex (RISC), assisted by other cofactors. In RISC, the mature miRNA interacts with its target messenger RNA to regulate gene expression via repression of translation or destabilization of messenger RNA. The complementary strand of miRNA, miRNA* (also called passenger strand), is degraded. Abbreviations: nts, nucleotides; Ago, Argonaute; pri-miRNA, primary miRNA; precursor miRNA, pre-miRNA; RISC, RNA-induced silencing complex.

Figure 2

A regulatory circuitry of estrogen-activated estrogen receptor (ER), estrogen-regulated microRNA (miRNA), and messenger RNA in estrogen action. Notes: Estrogen regulates miRNA expression at the transcriptional level through the direct binding of activated estrogen receptor to estrogen receptor binding site of the promoter of miRNA genes (a) or through the induction of estrogen-regulated transcription factors such as c-Myc (b). In addition, estrogen could regulate miRNA at the post-transcriptional level via affecting miRNA biogenesis (c). On the other hand the estrogen-regulated miRNAs can target estrogen receptor (d) and estrogen-responsive genes (e), thereby form a negative feedback loop to fine-tune estrogen-mediated cellular responses. Abbreviations: E2, estrogen; ER, estrogen receptor.