Academic journal article Genetics

Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis Elegans Somatic Tissues

Academic journal article Genetics

Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis Elegans Somatic Tissues

Article excerpt

MULTICELLULAR organisms rely on sophisticated gene expression programs to confer tissue identity and maintain homeostasis. The mRNA molecule is a dynamic mediator of these programs as it is capable of transferring genetic information into many different isoforms that shape gene expression outputs and precisely direct protein expression. However, in most cases, the dynamics of mRNA expression in the somatic tissues of living organisms that give rise to their specialized functions are still not clear. Thus, mapping tissuespecific transcriptomes of living organisms to identify gene isoforms and their expression levels is key to understanding the how mRNA coordinates development in normal states, and how its expression is disrupted in disease.

The small nematode Caenorhabditis elegáns is useful for such studies, since it has a complete cell-lineage map (Sulston et al. 1983), its development is well studied at the physiological and molecular level (Chalfie et al. 1981; Sternberg and Horvitz 1984), it has small, relatively simple tissues, and its transcriptome has been extensively characterized (Gerstein et al. 2010; Ramani et al. 2011). Its soma is composed of tissue groups commonly found in all metazoans, including muscle, epidermal, epithelial, and neuronal tissues. C. elegans has only two muscle tissues (pharynx and body muscle), and two distinct epidermal tissues (hypodermis and seam cells). Its epithelium includes the larger intestine tissue and small connective tissues, such as the arcade and intestinal valve (AIV) cells. C. elegáns also has a small, yet intricate nervous system composed of 302 cells in adult hermaphrodites, characterized by a range of neural cell types with unique information transmitting abilities.

In recent years, several biochemical approaches were used to isolate, map, and study tissue-specific transcriptomes in C. elegáns. These studies profiled transcriptome changes spanning from large tissues such as intestine (Pauli et al. 2006; McGhee et al. 2007; Haenni et al. 2012), to smaller tissues composed of just a few cells, such as sensory neurons (Takayama et al. 2010). Although such studies have relied on technologies with limited resolution and less reliable quantification (microarrays or tiling arrays), they have highlighted an unexpected complexity of gene regulatory mechanisms used by cells to maintain their tissue identity and to perform their biological roles.

Thus, the application of contemporary sequencing technologies to map and study tissue-specific transcriptomes may greatly expand our understanding of the regulatory mechanisms that establish and maintain cellular identity.

In addition to gene expression levels, small regulatory molecules such as microRNAs (miRNAs) can act as switches for complex developmental regulatory pathways (Lee et al. 1993; Reinhart et al. 2000; Yoo and Greenwald 2005; Cochella and Hobert 2012; Ebert and Sharp 2012). MiRNAs are short noncoding RNAs that guide the interaction between the RNA-induced silencing complex and target mRNAs by complementary base pairing ("seed"), primarily within the 3'untranslated region (3'UTR) of mRNAs, and typically hold the mRNA targets in translational repression (Bartel 2009). 3'UTRs are the portion of mature mRNAs located between the STOP codon and the poly(A)-tail, and play important roles in the regulation of gene expression (Bartel 2009). MiRNAs and their 3' UTR targets are frequently conserved, and play a variety of roles in regulating fundamental biological processes across metazoans. Recently, several groups have produced tissue-specific localization data for many miRNAs in mouse, rat, and human tissues (Eisenberg et al. 2007; Landgraf et al. 2007), and in cancer (Jima et al. 2010). These results unequivocally show that there are indeed distinct functional miRNA populations in tissues that are, in principle, capable of reshaping transcriptomes and contributing to cell identity acquisition and maintenance. Unfortunately, the tissue-specific gene regulatory networks targeted by miRNAs in living organisms are mostly not known. …

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