Mammalian gene regulation through the 3' UTR
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2008
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| Online Access: | http://hdl.handle.net/1721.1/42947 |
| _version_ | 1826215942221201408 |
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| author | Nielsen, Cydney Brooke |
| author2 | Christopher B. Burge. |
| author_facet | Christopher B. Burge. Nielsen, Cydney Brooke |
| author_sort | Nielsen, Cydney Brooke |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008. |
| first_indexed | 2024-09-23T16:39:54Z |
| format | Thesis |
| id | mit-1721.1/42947 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:39:54Z |
| publishDate | 2008 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/429472019-04-11T01:19:40Z Mammalian gene regulation through the 3' UTR Nielsen, Cydney Brooke Christopher B. Burge. Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Dept. of Biology. Biology. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008. This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Includes bibliographical references. The untranslated region (UTR) at the 30 end of a mammalian mRNA is typically rich with regulatory motifs that influence the stability, localization, translation and other properties of the message. We explored two classes of motifs, microRNA (miRNA) complementary sites and cleavage and polyadenylation (poly(A)) signals, and provide evidence that specific sequence contextual features are important for their recognition. MiRNAs are 22 nt, non-coding RNAs that function as post-transcriptional gene regulators in animals and plants. They typically interact with target mRNAs through base-pairing predominantly between bases 2-8 (the 'seed' region) at the 50 end of the miRNA and complementary sites in the target 30 UTR ('seed matches'). These interactions result in target mRNA translational repression or deadenylation, or both. Through analysis of mRNA expression data following miRNA or siRNA overexpression or inhibition, we uncovered novel targeting determinants that influence mRNA levels. These include the presence of distinct seed match types and sequence context, in particular that increased AU content and conservation were independently associated with greater target down-regulation. Our results demonstrate that mRNA fold change increases multiplicatively (i.e., log-additively) with seed match count. We integrated these features into a target scoring scheme, TargetRank, and demonstrated the effectiveness of our rankings in predicting in vivo target responses. Mammalian genes frequently have multiple, competing poly(A) sites, and the features influencing site selection remain poorly understood. Poly(A) site recognition occurs co-transcriptionally and given that transcription is highly influenced by the tight packaging of genomic DNA into chromatin, we investigated the potential impact of nucleosome positioning on poly(A) site usage. Using recent, public, Illumina sequencing data from human nucleosome boundaries, we found evidence that greater nucleosome density in regions flanking but not overlapping poly(A) sites is associated with more frequent usage. by Cydney Brooke Nielsen. Ph.D. 2008-11-07T14:12:56Z 2008-11-07T14:12:56Z 2008 2008 Thesis http://hdl.handle.net/1721.1/42947 259233162 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 196 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Nielsen, Cydney Brooke Mammalian gene regulation through the 3' UTR |
| title | Mammalian gene regulation through the 3' UTR |
| title_full | Mammalian gene regulation through the 3' UTR |
| title_fullStr | Mammalian gene regulation through the 3' UTR |
| title_full_unstemmed | Mammalian gene regulation through the 3' UTR |
| title_short | Mammalian gene regulation through the 3' UTR |
| title_sort | mammalian gene regulation through the 3 utr |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/42947 |
| work_keys_str_mv | AT nielsencydneybrooke mammaliangeneregulationthroughthe3utr |