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The role of alternative polyadenylation in secretory cell differentiation & in mRNA localization to the endoplasmic reticulum
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TitleInfo
Title
The role of alternative polyadenylation in secretory cell differentiation & in mRNA localization to the endoplasmic reticulum
Name
(type = personal)
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Cheng
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(type = given)
Larry Chen
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Larry Chen Cheng
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author
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(type = personal)
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Douglas
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Nataki
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Nataki Douglas
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Advisory Committee
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(authority = RULIB)
chair
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Tian
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Bin
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Bin Tian
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Advisory Committee
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(authority = RULIB)
internal member
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(type = family)
Xing
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(type = given)
Jinchuan
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Jinchuan Xing
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Advisory Committee
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(authority = RULIB)
internal member
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(type = personal)
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(type = family)
Tyagi
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(type = given)
Sanjay
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Sanjay Tyagi
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Advisory Committee
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(authority = RULIB)
outside member
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Rutgers University
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degree grantor
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School of Graduate Studies
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school
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Text
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theses
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ETD doctoral
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2021
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2021-05
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2021
Language
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English
Abstract
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Most eukaryotic genes produce alternative polyadenylation (APA) isoforms. Unlike in previously characterized cell lineages, differentiation of syncytiotrophoblast (SCT), a cell type critical for hormone production and secretion during pregnancy, elicits widespread transcript shortening through APA in 3’UTRs and in introns. This global APA change is observed in multiple in vitro trophoblast differentiation models, and in single cells from placentas at different stages of pregnancy. Strikingly, the transcript shortening is unrelated to cell proliferation, a feature previously associated with APA control, but instead accompanies increased secretory functions. We show that 3’UTR shortening leads to transcripts with higher mRNA stability, which augments transcriptional activation, especially for genes involved in secretion. Moreover, this mechanism, named secretion-coupled APA (SCAP), is also executed in B cell differentiation to plasma cells. Together, our data indicate that SCAP tailors the transcriptome during formation of secretory cells, boosting their protein production and secretion capacity.
Transcripts encoding membrane and secreted proteins undergo translation on endoplasmic reticulum (ER). By using cell fractionation, polysome profiling, and 3’ end sequencing, we examine translation-independent ER association (TiERA) of poly(A)+ RNAs. We show different functional gene groups have distinct TiERA potentials, and transcript size and sequence motifs are determinants of TiERA. APA isoforms differ substantially in TiERA, with long 3’UTR isoforms generally having a higher TiERA potential than short ones, highlighting a role of 3’UTR in TiERA control. The widespread 3’UTR lengthening in cell differentiation leads to greater transcript association with ER, especially for genes whose isoforms differ substantially in size. Moreover, TiERA inversely correlates with mRNA stability, suggesting distinct mRNA decay mechanisms on ER versus in cytosol. Together, our data indicate that transcript features diversify TiERA among genes, leading to distinct mRNA metabolism, and APA alters ER association of gene transcripts because of TiERA difference between isoforms.
Transcripts encoding membrane and secreted proteins undergo translation on endoplasmic reticulum (ER). By using cell fractionation, polysome profiling, and 3’ end sequencing, we examine translation-independent ER association (TiERA) of poly(A)+ RNAs. We show different functional gene groups have distinct TiERA potentials, and transcript size and sequence motifs are determinants of TiERA. APA isoforms differ substantially in TiERA, with long 3’UTR isoforms generally having a higher TiERA potential than short ones, highlighting a role of 3’UTR in TiERA control. The widespread 3’UTR lengthening in cell differentiation leads to greater transcript association with ER, especially for genes whose isoforms differ substantially in size. Moreover, TiERA inversely correlates with mRNA stability, suggesting distinct mRNA decay mechanisms on ER versus in cytosol. Together, our data indicate that transcript features diversify TiERA among genes, leading to distinct mRNA metabolism, and APA alters ER association of gene transcripts because of TiERA difference between isoforms.
Subject
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Topic
Quantitative Biomedicine
Subject
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Topic
Alternative polyadenylation
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Rutgers University Electronic Theses and Dissertations
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ETD_11632
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1 online resource (xiii, 134 pages) : illustrations
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Ph.D.
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Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier
(type = doi)
doi:10.7282/t3-8vkr-w512
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Cheng
GivenName
Larry
Role
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Permission or license
DateTime
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2021-03-28 23:01:10
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Name
Larry Cheng
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Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Embargo
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2021-05-31
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2023-05-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2023.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2021-03-29T02:34:46
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2021-03-29T02:34:46
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