Dissertation

MicroRNA Function in Zebrafish Development and Regeneration

Kara, Nergis

2018

Overview

MicroRNA (miRNAs) are evolutionarily conserved, small non-coding RNAs that post-transcriptionally regulate gene expression. They were initially identified in forward genetic screens in C. elegans as regulators of developmental timing (Lee et al., 1993; Wightman et al., 1993). Later, they were also discovered in plants, flies and vertebrates, involved in nearly all developmental and pathological processes (Ambros, 2003; Chen et al., 2005; Lagos-Quintana et al., 2003; Pasquinelli et al., 2000). As of March 2018, the miRNA registry (http://www.mirbase.org/) contained 38,589 miRNAs in vertebrates and invertebrates, with 2588 annotated miRNAs in the human genome; although biological functions of most of these miRNAs remain to be discovered (Griffiths-Jones et al., 2006). miRNA-mediated gene silencing involves two main components, miRNAs baseparing with their target mRNAs in complex with Argonaute (AGO) proteins thereby recruiting factors that initiate translational repression as well as mRNA deadenylation and decay (Huntzinger and Izaurralde, 2011). miRNA binding sites are generally located in the 3’ untranslated region (UTR) of mRNAs and referred as miRNA recognition elements (MREs) (Bartel, 2009). For target recognition, the crucial region on the miRNA is located from nucleotides 2 to 7 and termed as the ‘miRNA seed’. Meanwhile, the nucleotides downstream of the seed sequence are involved in additional imperfect basepairing of the miRNA with the target mRNA. In the human genome, more than 60% of protein-coding genes carry at least one conserved MRE. When non-conserved MREs are also taken into consideration, most protein-coding genes are thought to be regulated by miRNAs (Friedman et al., 2009). While miRNAs can bind to many target mRNAs, multiple miRNA can also target the same mRNAs. This characteristic makes miRNAs unique potent regulators of gene expression. Thus, the biogenesis and function of miRNAs themselves are tightly regulated as well. Due to gene duplication in the genomes of many species, there are multiple related miRNA loci with related sequences. miRNAs with identical seed sequences are generally referred as ‘miRNA families’ (Bartel, 2009). One example is the let-7 family which consists of 14 paralogous loci in the human genome. miRNA family members generally have redundant functions, although some distinct roles have been reported as well (Ha and Kim, 2014). Some miRNAs may share common evolutionarily origins, but nevertheless diverge in their seed sequences. One such example is miR-141 and miR- 200c miRNAs that derived from miR-200 superfamily but their seed sequences vary by 1 nucleotide. It has been shown that targets of miR-141 and miR-200c do not overlap; therefore each miRNA has distinct functions (Kim et al., 2013). (Shortened by ProQuest.)

• Publisher: ProQuest Dissertations & Theses
• Subject: Developmental biology
• ISBN: 9781392061107, 1392061105