The role of alternative polyadenylation in secretory cell differentiation & in mRNA localization to the endoplasmic reticulum
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Cheng, Larry Chen.
The role of alternative polyadenylation in secretory cell differentiation & in mRNA localization to the endoplasmic reticulum. Retrieved from
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TitleThe role of alternative polyadenylation in secretory cell differentiation & in mRNA localization to the endoplasmic reticulum
Date Created2021
Other Date2021-05 (degree)
Extent1 online resource (xiii, 134 pages) : illustrations
DescriptionMost 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.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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