Functions of Argonaute Proteins in Self Versus Non-Self Recognition in the C. elegans Germline: A Dissertation
Authors
Seth, MeetuFaculty Advisor
Craig C. MelloAcademic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
RNA Therapeutics InstituteDocument Type
Doctoral DissertationPublication Date
2016-08-18Keywords
Dissertations, UMMSRNA Interference
RNA, Small Interfering
Argonaute Proteins
Caenorhabditis elegans Proteins
RNA Interference
Small Interfering RNA
Argonaute Proteins
Caenorhabditis elegans Proteins
Biochemistry
Developmental Biology
Genetics and Genomics
Molecular Biology
Metadata
Show full item recordAbstract
Organisms employ sophisticated mechanisms to silence foreign nucleic acid, such as viruses and transposons. Evidence exists for pathways that sense copy number, unpaired DNA, or aberrant RNA (e.g., dsRNA), but the mechanisms that distinguish “self” from “non-self” are not well understood. Our studies on transgene silencing in C. elegans have uncovered an RNA surveillance system in which the PIWI protein, PRG-1, uses a vast repertoire of piRNAs to recognize foreign transcripts and to initiate epigenetic silencing. Partial base pairing by piRNAs is sufficient to guide PRG-1 targeting. PRG-1 in turn recruits RdRP to synthesize perfectly matching antisense siRNAs (22G-RNAs) that are loaded onto worm-specific Argonaute (WAGO) proteins. WAGOs collaborate with chromatin factors to maintain epigenetic silencing (RNAe). Since mismatches are allowed during piRNA targeting, piRNAs could—in theory— target any transcript expressed in the germline, but germline genes are not subject to silencing by RNAe. Moreover, some foreign sequences are expressed and appear to be adopted as “self.” How are “self” transcripts distinguished from foreign transcripts? We have found that another Argonaute, CSR-1, and its siRNAs—also synthesized by RdRP—protect endogenous genes from silencing by RNAe. We refer to this pathway as RNA-mediated gene activation (RNAa). Reducing CSR-1 or PRG-1 or increasing piRNA targeting can shift the balance towards expression or silencing, indicating that PRG-1 and CSR-1 compete for control over their targets. Thus worms have evolved a remarkable nucleic acids immunity mechanism in which opposing Argonaute pathways generate and maintain epigenetic memories of self and non-self nucleotide sequences.DOI
10.13028/M2C30KPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32250Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2C30K
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