Sweta Rani - MicroRNA Profiling

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Springer Science+Business Media New York 2017

Sweta Rani (ed.) MicroRNA Profiling Methods in Molecular Biology 1509 10.1007/978-1-4939-6524-3_1

1. MiRNA Biogenesis and Regulation of Diseases: An Overview

Anchal Vishnoi 1 and Sweta Rani 2

(1)

SEQOME Ltd, Waterford, Ireland

(2)

Department of Science, Waterford Institute of Technology, Main Campus Cork Road, Waterford, Ireland

Sweta Rani

Email:

Abstract

MicroRNAs (miRNAs) are small RNA molecules, with their role in gene silencing and translational repression by binding to target mRNAs. Since it was discovered in 1993, miRNA are found in all eukaryotic cells conserved across the species. In recent years, regulation of miRNAs are extensively studied for their role in biological processes as well as in development and progression of various human diseases including retinal disorder, neurodegenerative diseases, cardiovascular disease and cancer. This chapter summarises miRNA biogenesis and explores their potential roles in a variety of diseases. miRNAs holds huge potential for diagnostic and prognostic biomarkers, and as predictors of drug response.

Key words

miRNA Retinal disorder Neurodegenerative diseases Cardiovascular disease Cancer

Introduction

1.1 microRNAs (miRNA)

microRNA (miRNA) was first observed in Caenorhabditis elegans [].

Ambros and Ruvkun were the first to discover miRNA in 1993. Lin-4 was the first miRNA to be discovered in C. elegans [].

miRNA are small non-coding RNAs, single-stranded RNA molecules of approximately 2123 nucleotides in length. miRNA has a uridine at their 5-end and partially complementary to the 3 -end untranslated regions of the messenger RNA (mRNA). miRNA recruits Argonaute (AGO) protein complex to a complementary target mRNA, which results in translation repression or degradation or deadenylation of the mRNA [].

miRNA Biogenesis

2.1 Transcription of miRNA

The miRNA biogenesis in human follows a two step process with nuclear and cytoplasmic cleavage event. In the nucleus the miRNAs are transcribed as a long transcript called pri-miRNA, either by their own promoters or by sharing promoters of their host gene [].

Fig. 1

miRNA biogenesis in ( a ) animal and ( b ) plant. (1). RNA pol II responsible for the pri-miRNA transcription (2). Drosha RNase III endonuclease cleavs pri-miRNA near the base of the primary stem loop. In plant DCL1 has a siilar function as drosha. (3). The pre-miRNA transported into the cytoplasm (4). pre-miRNA maturation in the cytoplasm is carried out by RNase III endonuclease Dicer (5). The helicase domain recognises the loop region and cleaves both the strands (6). Short RNA fragment called miRNA (7). MiRNA bind to their target mRNA and negatively regulate its expression

miRNAs which resides in introns are known as mirtrons. Mirtrons presence is widespread in Drosophila, C. elegans , vertebrates and plants [).

2.2 Formation of pre-miRNA

The nuclear cleavage of the pri-miRNA, is carried out by Drosha RNase III endonuclease (Fig. 3).

2.3 Maturation of Pre-miRNA in Cytoplasm

The pre-miRNA maturation in the cytoplasm is further carried out by RNase III endonuclease Dicer (Fig. ).

Regulation of Dicer

Different pathways regulate Dicer, which in turn regulates the amount of miRNA in the cell. In human sometimes, the Dicer is regulated by its miRNA through the binding sites, as present in the let-7 miRNA [].

3.1 Maturation of miRNA in RISC

Both in plants and animals, the miRNA from the miRNAmiRNA* complex are loaded into RNA induced silencing complex (RISC). Further, maturation of miRNAs are carried out by the RISC-loading complex (RLC) [].

The Argonaute protein, a catalytic component of RISC helps in uptake of miRNA and freeing of Dicer. In some case, as in mammalian cells, Ago2, a Argonaute protein have endonuclease activity and cleave the 3 arm of the miRNA before being processed by Dicer, this in turn may help in determining the mature miRNA strand [].

The Argonaute proteins in addition to targeting the mRNA also regulate the stability of the miRNAs. In C. elegans by unknown mechanism the ALG-1 (Argonautes) play a role in miRNA stability and precursor processing [].

The addition of nucleotide at 3 end of miRNA does not always lead to its degradation. In mice, poly(A) polymerase GLD-2 determines the addition of single adenosine at the 3 end of the miR-122, which in turn protect it from the exonuclease activity and thus increasing its life [].

The miRNA biogenesis pathway is also regulated by other miRNA. For example, in mouse the miR-709 binds to the complimentary sites of primary miR-15a/16-1 and repress its Drosha processing []. Therefore, it can be said that there are different pathways, which degrade or stabilize the structure of miRNA altering its level in the cell.

Extracellular Vesicles (EVs)

Extracellular vesicles (EVs) are nano-sized (40100 nm in diameter) vesicles of endosomal origin [].

4.1 Role of EVs and miRNA in Diseases

With the discovery of miRNAs, it has garnered huge interest in determining their role in various diseases. Dysregulation of miRNA expression plays an important role in disease progression and their expression profiling is likely to become important diagnostic and prognostic tools. miRNA therapeutics is not only challenging but also promising for several diseases.

4.2 Retinal Disorder

miRNAs has been found to play essential roles in not only retinal development and survival, but also in their normal functioning. It is still not clear if every cell type has their own miRNA phenotype but studies have confirmed the presence of differentially expressed miRNA in neural retina and their expression patterns can be used to distinguish retinal cell types [].

miR-183/96/182 cluster provide a protective role in retinal neurons and inactivation of this cluster in transgenic mice resulted in gradual synaptic connectivity defects of the photoreceptors causing extreme sensitivity to light and severe retinal degeneration [].

4.3 Neuro-degenerative Diseases

Cause of central nervous system diseases could be attributed to the altered expression of miRNAs. Study of miRNA expression could lead to novel molecular information and therapeutic option including enhancing or inhibiting specific miRNAs to improve the disease treatment.

Earlier in 2012, Xin et al. demonstrated that MSCs communicate via exosomes with brain parenchymal cells and regulate neurite outgrowth by horizontal transfer of miR-133b to neural cells in vitro [].

4.4 Cardiovascular Disease

miRNAs plays an important role in the development of cardiac tissue at all stages [].

miRNAs associated with MSC-EVs also play an important role in cardio-protection and was found that miR-22-loaded EVs targeted methyl CpG binding protein 2 (Mecp2) promoting cardiac remodelling following myocardial infarction [].

4.5 Cancer

miRNAs are known as critical regulator of gene expression, and in cancer, miRNA play a role in oncogenesis, metastasis, and resistance to various therapies. miRNAs can be classified as oncogenes (oncomirs), tumor-suppressor genes, pro-metastatic (metastamiRs) and metastasis-suppressor [].

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