miRNA or micro RNA is a non-coding RNA molecule. It is a single-stranded small RNA molecule of about 22 nucleotides long. It plays a role in the regulation of gene expression and gene silencing. It is present naturally in plants, animals and some viruses.
miRNA was first discovered by Ambros, Lee, Feinbaum and the group. miRNAs are found in various types of mammalian cells. They are also found circulating in extracellular fluids such as blood and cerebrospinal fluid.
miRNA is complementary to mRNA and they silence genes by base pairing to the complementary mRNA molecule. They inhibit gene expression either by cleaving or destabilising mRNA or by reducing the efficiency of translation.
miRNA Biogenesis
Various small non-coding RNAs have been discovered recently that have a role to play in the regulation of gene expression, RNA processing, transcription, translation, RNA stability, etc. E.g. microRNA (miRNA), small interfering RNAs (miRNA), and piRNA.
miRNA is a single-stranded RNA molecule. It is around 21-25 nucleotides long. It is transcribed as long pre-miRNA, which undergoes cleavage and processing to form mature miRNA. miRNA is transcribed by RNA polymerase II and III. Many miRNA genes lie in the introns of other genes. The pre-miRNA is much longer and comprises the 5’ cap and 3’ poly(A) tail.
The pre-miRNA undergoes nuclear and cytoplasmic processing. miRNAs are derived from the hairpin loops in pre-miRNA transcripts. In the nucleus, pre-miRNA is processed by the enzyme Drosha. It has an RNase III domain to form a microprocessor complex.
In the cytoplasm, pre-miRNA is processed by another enzyme called Dicer. It is also an RNase III enzyme. It forms a miRNA duplex of 22 nucleotides. Either of the strands has the capability to act as a miRNA. In the RISC complex, only one strand is incorporated that targets the mRNA.
The biogenesis in plants differs from animals. In plants, Dicer homolog is responsible for both inside and outside nucleus processing.
Mechanism of Action
miRNA like siRNA is involved in gene silencing through RNA interference. It is involved in post-transcriptional gene silencing (PTGS).
The mature miRNA is associated with other proteins to form the RNA-Induced Silencing Complex (RISC). It is also referred to as miRISC. The processing of pre-miRNA by Dicer also causes unwinding of the duplex and only one miRNA strand is associated with the RISC complex. The other strand is generally degraded.
miRNA silences a gene either by degrading mRNA or by inhibiting the translation. It also destabilises mRNA by shortening the poly(A) tail.
Function and Application
The main function of miRNA is in gene regulation. miRNA may be complementary to one or more mRNAs. In animals, miRNAs are generally compatible with the 3’ untranslated regions, whereas, in plants, miRNAs are complementary to the coding regions.
In plants, base pairing is nearly perfect and it induces cleavage of mRNA. In animals, it is partially complementary to mRNA and inhibits mRNA translation and inhibits the synthesis of a gene product. It can also induce mRNA deadenylation leading to destabilisation of mRNA.
miRNA can also affect the expression of genes by methylation of DNA at the promoter site. It can also cause histone modifications.
miRNA are conserved during evolution and are useful phylogenetic markers. An animal miRNA can target various genes. They are well conserved therefore miRNAs are necessary for the normal functioning of a cell and gene regulation.
miRNA are also found to regulate the blood coagulation cascade and hemostasis. miRNA also regulates obesity, diabetes and insulin resistance. A class of miRNA is found to accumulate with ageing and induce insulin resistance leading to obesity and diabetes.
They regulate the genes involved in the cell cycle, cell signalling, apoptosis, nervous system development, etc. and are involved in the altered gene expression during addiction.
Many diseases such as Alzheimer’s, schizophrenia, depression and anxiety disorders are found to have an altered miRNA expression. It is also involved in the regulation of cholesterol metabolism and is involved in cardiomyopathies during cardiovascular diseases and stroke.
miRNA dysregulation is associated with various inherited diseases, e.g. cataract, progressive hearing loss, skeletal and growth defects, etc. The miRNA dysregulation has been associated with chronic lymphocytic leukemia, a type of cancer. It is also found to be associated with colorectal cancer. The interaction of miRNA with the tumour suppressor gene is linked to the proliferation of hepatocellular carcinoma cells.
miRNA are also known to work as a tumour antagonist. miRNA can be used as targets or tools for the treatment of various cancers. miRNA regulates many genes involved in DNA repair. When the DNA repair mechanism is defective, it leads to the accumulation of mutations and leads to cancer. The abnormal expression of miRNA genes involved in DNA repair has been linked to causing various types of cancers.
Viral miRNA plays an important role in gene regulation of viruses as well as host to benefit the virus. It plays a key role in the pathogenesis of the viral disease.
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