Wednesday, June 11, 2008

MicroRNAs

MicroRNAs – Small RNAs with Large Potential and Several Complexities
Manoj Hariharan

In the genome, non-coding sequences are widely interspersed within and between genes and complicate gene annotation. Although their importance has been widely appreciated for past few decades, the functional relevance of non-coding sequences is still not well understood. Moreover, a growing number of non-coding sequences are found to be transcribed into small RNAs with unknown functions.A novel class of such small molecules, viz. MicroRNAs (miRNAs) and other non-coding RNAs that are not translated to proteins have been found to operate at several levels of genomic architecture regulating chromatin formation, RNA editing, RNA stability and efficiency of mRNA-translation. While identifying and annotating miRNAs is tricky, these possess a structural peculiarity such as a imperfect hairpin structures which makes the task easier. Such a feature includes a palindromic nucleotide sequence interrupted by 5-10 non self-complementary bases giving rise to a hairpin with a stem of length ranging from 20-40bases. This type of molecule is an ideal candidate for a precursor miRNA. There now exist several computational programs that allow identifying such sequences in the genome and most miRNAs identified so far do exhibit these features.

Here, I shall briefly describe the current understanding of miRNA mediated regulation and the changing trends in this knowledge. Nearly 100-base-long transcripts or precursor miRNA (pre-miRNA) are processed to form ~17-25 nucleotides long mature miRNAs. These are encoded in the DNA either as clusters of primary miRNA (pri-miRNA) which could be as long as 1 kb or shorter stretches in the “intergenic” as well as “genic” regions. The earliest attempts at uncovering the regulatory potential of such small RNAs revealed finer difference in the mode of action of miRNA and small interfering RNA (siRNA). The siRNA bind to the entire target transcript while the miRNA bind to mostly the 3’ UTR of the target transcripts through imperfect complementarity creating stretches of continuous matches towards the 5’ end of miRNA, termed seed matches, and bulges of 1-4 nucleotides with a favorable Minimal Free Energy (MFE). This binding dramatically reduces the translational efficiency of the target transcript. Furthermore, a particular miRNA may interact with several transcripts (multiplicity) or it can be targeted by more than one miRNA (co-operativity). Given the number of miRNAs expressed in each metazoan genome and some viruses this generates a large regulatory potential. Humans encode over 650 miRNAs. Several approaches identifying the targets of these miRNAs, in silico, in vitro and in vivo have allowed understanding the regulatory potential of miRNAs during development, stress, cancer, apoptosis and host-pathogen interaction.

At the Institute of Genomics & Integrative Biology, CSIR, India, we have established a massive program to uncover the regulatory potential of miRNAs in various biological processes and in multiple experimental models backed by a strong in silico approach. We have developed computational tools to identify miRNAs, second generation target-prediction tools, miRNA expression profiling as well as miRNA-target databases that are available at http://miracle.igib.res.in/


07 June, 2008.

1 Comments:

Blogger sohan modak said...

Nice, Manoj! Do note that miRNAs, as noncoding sequences, represent an intriguing set of appendages to the genetic grammar and invoke 'context-based' semantics that allows regulation as well as fine tuning of the flow of genetic information.

sohan modak

June 13, 2008 9:06 AM  

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