MicroRNA processing
The precursors of miRNAs are transcribed from DNA. The processing of miRNAs from primary miRNA transcripts (pri-miRNA) into precursor miRNAs (pre-miRNA) and then into mature miRNAs are mediated by the enzymes Drosha in the nucleus and Dicer in the cytoplasm espectively. The mature miRNA will then associate with a complex called RNA Induced Silencing Complex (RISC). Picture from ambion.com demonstrates the main miRNA processing pathway. Quite recently, a dicer-independent pathway for maturation of miRNA has also been reported (Nature, 29 Apr 2010).
Mechanism of action
Posttranscription
The translational repression has been accepted as the main mechanism by which mature miRNAs contribute to the regulation of endogenous genes' activities. This is mainly via targeting specific region in the 3’untranslated regions (UTR) of messenger RNAs (mRNA), which are usually partially complementary to miRNAs. There are evidences supporting the idea that miRNAs can also positively regulate protein expression.
Transcription
Apart from their roles as posttranscriptional regulators, miRNAs have been shown to exert direct effects on the gene expression via histone modification and DNA methylation of target genes' promoters. MicroRNAs may also indirectly regulate the transcriptional activation of a gene via targeting the related transcription factors and even coactivators.
MicroRNAs and Immune System
MicroRNAs are involved in the regulation of immune system including the development of lymphocytes, the generation of cytokines and antibodies, and proliferation of monocytes and neutrophils etc. It has been reported that disruption of Dicer gene in mice leads to lethality early in development, indicating the importance of miRNAs in embryonic development. However, specific inactivation of Dicer in the T cell lineage didn’t lead to lethality. But it has been shown to be associated with impaired T cell development, aberrant T helper cell differentiation and cytokine production. These observations indicate the importance of miRNAs in the immune system via regulating, at least in part, the development, differentiation and function of T cells.
MicroRNAs are involved in the regulation of both innate and adaptive immune responses. For example the Toll-like receptors, which recognize the bacterial constituents and viral nucleic acids has been reported to induce expression of some miRNAs, which in turn regulate expression of proteins involved in the innate immune responses.
According to a latest report published in Nature Cell Biology 12 (2010), some miRNAs can regulate innate antiviral immunity by inhibiting expression of the p300 co-activator, which interact with transcription factors and contributes to gene expression. Thus, miRNAs might have a broad role in the regulation of antiviral immunity.
MicroRNAs in diseases
In addition to their roles in the regulation of immune responses, miRNAs has also been shown to be involved in the pathogenesis of different types of cancers including leukemias and lymphomas. This is due to the regulatory roles of miRNAs in physiologic processes including cell proliferation and cell death (apoptosis). Different studies have also elucidated the role of miRNAs in immune tolerance and autoimmunity. For example, selective miRNA disruption in T-regulatory cells has been reported to cause uncontrolled autoimmunity. In some recent studies, a functional connection between miRNA expression and allergic diseases such as asthma has been reported. Thus, targeting some miRNAs has been suggested as a method for the treatment of allergic airway inflammation. Elucidation of the roles of few hundred human miRNAs in health and diseases, in combination with many virally-encoded miRNAs, which regulate expression of viral as well as cellular genes, has been a great challenge for the researchers, especially for therapeutic purposes.
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