Pasquinelli, Amy - University of California, San Diego

研究领域

The recent discovery of microRNAs (miRNAs) has revolutionized our understanding of gene control. Genetic studies in the nematode Caenorhabditis elegans (Figure 1) revealed the first members of what we now recognize as an extensive family of regulatory RNAs that exist in most multicellular organisms. Already there is evidence that specific miRNAs play key roles in controlling development, stem cell fates and neuronal differentiation, and mutations in human miRNA genes have been linked to oncogenic and other disease states. The Pasquinelli lab couples C. elegans genetics with molecular and biochemical techniques to understand the basic mechanisms of miRNA expression and function and to elucidate the biological roles of specific miRNAs in cellular differentiation programs. How is the expression of miRNAs regulated? MiRNA genes typically encode long primary transcripts (pri-miRNAs) that undergo multiple processing steps to generate the mature ~22 nucleotide miRNA (Figure 2). Many miRNA genes are expressed at precise times in development and in specific tissues. To understand how these temporal and spatial expression patterns are achieved, we study the transcriptional and processing events that cooperate to produce specific miRNAs at the right time and in the right place. How do miRNAs regulate gene expression? The miRNAs regulate specific genes by partially base-pairing to complementary sequences in the messenger RNAs (mRNAs) of protein-coding genes (Figure 2). The human genome contains over 700 different miRNA genes, each of which may directly regulate hundreds of protein coding genes. To help elucidate how miRNAs find and regulate targets with limited sequence complementarity, we have focused on specific miRNA genes and have performed genome wide analyses to identify potential targets. Regulation by miRNAs can result in degradation or translational repression of the target mRNA (Figure 2), but the molecular mechanisms behind these inhibitory strategies are not entirely understood. By studying defined miRNA and target pathways in C. elegans, my lab aims to elucidate how miRNAs control gene expression in the endogenous context. What is the biological function of miRNA regulatory pathways? Some miRNA genes, like let-7, are essential for normal development (Figure 1). The let-7 miRNA and its temporally regulated expression pattern are widely conserved across animal phylogeny and misexpression of this miRNA has been linked to cancer in humans. A goal of our studies on the worm let-7 gene is to understand the broad role let-7 plays in cellular differentiation events across species.

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Pasquinelli AE. A rADAR defense against RNAi. Genes Dev, 2018 Feb 1;32(3-4):199-201. Aalto AP, Nicastro IA, Broughton JP, Chipman LB, Schreiner WP, Chen JS, Pasquinelli AE. Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging. PLoS Genet. 2018 Jun 21;14(6):e1007379. doi: 10.1371/journal.pgen.1007379. eCollection 2018 Jun. Broughton JP, Pasquinelli AE. Detection of microRNA-Target Interactions by Chimera PCR (ChimP). Methods Mol Biol. 2018;1823:153-165. doi: 10.1007/978-1-4939-8624-8_12. Azoubel Lima S, Chipman LB, Nicholson AL, Chen YH, Yee BA, Yeo GW, Coller J, Pasquinelli AE. Short Poly(A) Tails are a Conserved Feature of Highly Expressed Genes, Nat Struct Mol Biol, 2017 Dec;24(12):1057-1063. doi: 10.1038/nsmb.3499. Epub 2017 Nov 6. Schreiner WP and Pasquinelli AE. Making and Maintaining MicroRNAs in Animals, Chapter for “Essentials of microRNAs in neurogenesis: ontogenesis and plasticity of the mammalian neural system” 1st Ed. De Pietri Tonelli, Elsevier, 2017. Pasquinelli AE. A sense-able microRNA. Genes Dev, 2016 Sep 15;30(18):2019-2020. Broughton JP, Lovci MT, Huang JL, Yeo GW, Pasquinelli AE. Pairing Beyond the Seed Supports MicroRNA Targeting Specificity. Mol Cell, 2016 Oct 20:64:1-14. Broughton JP, Pasquinelli AE. A tale of two sequences: microRNA-target chimeric reads. Genet Sel Evol. 2016 Apr 4;48:31. doi: 10.1186/s12711-016-0209-x. Review. Van Wynsberghe PM, Pasquinelli AE. Period Homolog LIN-42 regulates miRNA transcription to impact developmental timing. Worm, 2014 3(4)e974453. Mondol V, Ahn BC, Pasquinelli AE. Splicing remodels the let-7 primary microRNA to facilitate Drosha processing in Caenorhabditis elegans. RNA, 2015 21(8):1396-1403 Pasquinelli AE. MicroRNAs: heralds of the non-coding RNA revolution. RNA, 2015. 21(4):709-710. Mondol V, Ahn BC, Pasquinelli AE. Splicing remodels the let-7 primary microRNA to facilitate Drosha processing in Caenorhabditis elegans. RNA, 2015 21(8):1396-1403. Van Wynsberghe PM, Finnegan EF, Stark T, Angelus EP, Homan KE, Yeo GW, Pasquinelli AE. The Period protein homolog LIN-42 negatively regulates microRNA biogenesis in C. elegans. Dev Biol. 2014 Jun 15;390(2):126-35. Fonslow BR, Moresco JJ, Tu PG, Aalto AP, Pasquinelli AE, Dillin AG, Yates Iii JR. Mass spectrometry-based shotgun proteomic analysis of C. elegans protein complexes. WormBook. 2014 Jun 24:1-18. doi: 10.1895/wormbook.1.171.1. Lima SA, Pasquinelli AE. Identification of miRNAs and their targets in C. elegans. Adv Exp Med Biol. 2014; 825:431-50. Van Wynsberghe PM, Pasquinelli AE. Period Homolog LIN-42 regulates miRNA transcription to impact developmental timing. Worm, 2014 3(4)e974453. Finnegan EF, Pasquinelli AE. MicroRNA biogenesis: Regulating the regulators. Critical Reviews In Biochemistry & Molecular Biology, 2013 Jan-Feb;48(1):51-68. PMC3557704 Kai, ZS, Finnegan EF, Huang S, Pasquinelli AE. Multiple cis-elements and trans-acting factors regulate dynamic spatio-temporal transcription of let-7 in Caenorhabditis elegans. Dev Biology, 2013 Feb 1;374(1):223-33. PMC3548979 Massirer KB, Pasquinelli AE. MicroRNAs that interfere with RNAi. Worm, 2013 Jan/Feb/Mar;2(1):e1-6. Hunter SE, Finnegan EF, Zisoulis DG, Lovci MT, Melnik-Martinez KV, Yeo GW, Pasquinelli AE. Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans. PLoS Genetics, 2013 Mar;9(3)e1003353. PMC3597506 Broughton JP, Pasquinelli AE. Identifying Argonaute binding sites in Caenorhabditis elegans using iCLIP. Methods, 2013 Apr 10. S1046-2023(13)00102-3. Pasquinelli AE. The primary target of let-7 miRNA. Biochem. Soc. Trans. 2013 Aug 1;41(4):821-4. Pasquinelli AE. A team effort blocks the ribosome in its tracks. Nat Struct Mol Biol. 2012 19(2):133-4. Mondol V, Pasquinelli AE. Let’s make it happen: The role of let-7 microRNA in development. In Eran Hornstein, editors: MicroRNAs in Development, CTDB, UK: Academic Press, 2012, 99:1-30.