MicroRNA Systems Biology

Edwin Wang

1. Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montreal, Quebec, Canada, and 2. Center for Bioinformatics, McGill University, Montreal, Quebec, Canada

Email: Edwin.Wang@cnrc-nrc.gc.ca Fax : 1-514-496-5143 Tel : 1-514-496-0914

More similar work can be found at: www.bri.nrc.ca/wang

1 Abstract Recently, microRNAs (miRNAs) have emerged as central posttranscriptional regulators of gene expression. miRNAs regulate many key biological processes, including cell growth, death, development and differentiation. This discovery is challenging the central dogma of molecular biology. Genes are working together by forming cellular networks. It has become an emerging concept that miRNAs could intertwine with cellular networks to exert their function. Thus, it is essential to understand how miRNAs take part in cellular processes at a systems-level. In this review, I will first introduce basic knowledge of miRNAs and their relations to heart disaeses and cancer, highlight recently dicovered functions such as filtering out gene expression noise by miRNAs. I will aslo introduce basic concepts of cellular networks and interpret their biological meaning in such a way that the network concepts are digested in a biological context and are understandable for biologists. Finally, I will summarize the most recent progress in understanding of miRNA biology at a systems-level: the principles of miRNA regulation of the major cellular networks including signaling, metabolic, protein interaction and gene regulatory networks. A common miRNA regulatory principle is emerging: miRNAs preferentially regulated the genes that have high regulation complexity. In addition, miRNAs preferentially regulate positive regulatory motifs, highly connected scaffolds and the most network downstream components of cellular signaling networks, while miRNAs selectively regulate the genes which have specific network structural features on metabolic networks.

2 1.1 Introduction According to the central dogma of molecular biology, RNAs are passive messengers and only take charge of transferring genetic information, or carrying out DNA instructions, or code, for protein production in cells. However, this central dogma is getting challenged by the recent findings that tiny fragments of noncoding RNA, typically ~22 nucleotides in length, namely microRNA (miRNA), are able to negatively regulate protein-coding genes by interfering with mRNA’s original instructions. Recent studies indicate that miRNAs have emerged as central posttranscriptional repressors of gene expression. miRNAs suppress gene expression via imperfect base pairing to the 3′ untranslated region (3′UTR) of target mRNAs, leading to repression of protein production or mRNA degradation (Bartel, 2004; Carthew, 2006; Valencia-Sanchez et al. 2006). These noncoding regulatory RNA molecules have been found in diverse plants, animals, some viruses and even algae species and it now seems likely that all multicellular eukaryotes, and perhaps some unicellular eukaryotes, utilize these RNAs to regulate gene expression.

Some researchers claimed that the human genome might encode more than 1,000 miRNAs (Bentwich et al. 2005), however, a recent sequencing survey of miRNA expression cross 26 distinct organ systems and cell types of human and rodents validated that only over 300 miRNAs are present in humans and/or rodents (Landgraf et al. 2007). Computational predictions indicate that thousands of genes could be targeted by miRNAs in mammals (John et al. 2004; Krek et al. 2005; Lewis et al. 2003; Rajewsky, 2006). Experimental analysis revealed that 100 to 200 target mRNAs are repressed and destabilized by a single miRNA (Krutzfeldt et al. 2005; Lim et al. 2005; Yu et al. 2007a). It is estimated that more than one third of human genes are potentially regulated by miRNAs. These findings suggest that miRNAs play an integral role in genome-wide regulation of gene expression.

miRNAs regulate many key biological processes, including cell growth, death, development and differentiation, by determining how and when genes turn on and off. Animals that fail to produce certain mature miRNAs are unable to survive or reproduce (Bernstein et al. 2003; Forstemann et al. 2005; Ketting et al. 2001; Wienholds et al. 2003; Cao et al. 2006; Plasterk, 2006; Shivdasani, 2006). Thus, a single, malfunctioning microRNA can be sufficient to cause cancer in mice (Costinean et al. 2006). These discoveries offer new insight into another layer of gene regulation and at the same time underscore the powerful role that these tiny snippets of non-coding RNA play in cells. These discoveries indicate that it is no longer the genes, or mRNAs themselves that held the most intrigue, but the miRNAs that influence their behavior and the result that su

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