3' untranslated regions (3' UTRs) are the hubs of post-transcriptional regulation, and contain the majority of binding sites for regulatory factors such as miRNAs and RNA binding proteins (RBPs). Moreover, it has recently become appreciated that most genes do not express a single 3' UTR, but instead express multiple 3' UTR isoforms through a process known as alternative polyadenylation (APA). Since APA can be deployed to coordinately shift the 3' UTR profiles of large cohorts of genes according to tissue identity, environmental condition, or disease status, APA can broadly affect the post- transcriptional landscape and profoundly impact gene expression programs. Nevertheless, very little remains known about the underlying mechanisms of how global APA programs are enacted. In ongoing work, we identify conserved, redundant roles for Hu family neural RBPs in driving a broad program of neural 3' UTR lengthening in both Drosophila and mammalian nervous system. Here, we will use molecular genetic assays and genomewide analyses to elucidate the mechanism for neural Hu proteins in conferring neural 3' UTR extensions. Since neural Hu factors have such powerful capacity to remodel the transcriptome, it may follow that they are under strict control. Indeed, we have also found that neural Hu genes in both Drosophila and mammals are subject to unexpectedly complex and strong post-transcriptional suppression outside of the nervous system. We have developed new genetic models to study these regulatory mechanisms and their phenotypic impacts, which may reveal new roles for these factors in developmental patterning and also have tangible implications for a class of human disease that is caused by misexpression of neural Hu proteins outside of the brain. Overall, this work will reveal new perspectives on the deployment of the distinctive neural post-transcriptional landscape and its in vivo biological importance.

Public Health Relevance

It has recently become appreciated that alternative polyadenylation (APA) causes a majority of genes to express multiple 3'UTR isoforms, resulting in radical differences in post-transcriptional regimes. We are studying a conserved phenomenon by which 3'UTRs are broadly extended in the nervous system of Drosophila and vertebrates via Hu family RNA binding proteins (RBPs), and reciprocally, how the activity of Hu genes is restricted by powerful post-transcriptional mechanisms. This work informs how a defining feature of the distinctive neural transcriptome is generated, and more generally, may shed light on how 3'UTR landscapes can be altered by RBPs during disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS083833-08
Application #
10102285
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Riddle, Robert D
Project Start
2014-01-15
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Kavaler, Joshua; Duan, Hong; Aradhya, Rajaguru et al. (2018) miRNA suppression of a Notch repressor directs non-neuronal fate in Drosophila mechanosensory organs. J Cell Biol 217:571-583
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Zhou, Li; Lim, Mandy Yu Theng; Kaur, Prameet et al. (2018) Importance of miRNA stability and alternative primary miRNA isoforms in gene regulation during Drosophila development. Elife 7:
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Kondo, Shu; Vedanayagam, Jeffrey; Mohammed, Jaaved et al. (2017) New genes often acquire male-specific functions but rarely become essential in Drosophila. Genes Dev 31:1841-1846
Lin, Ching-Jung; Wen, Jiayu; Bejarano, Fernando et al. (2017) Characterization of a TUTase/RNase complex required for Drosophila gametogenesis. RNA 23:284-296
Sanfilippo, Piero; Wen, Jiayu; Lai, Eric C (2017) Landscape and evolution of tissue-specific alternative polyadenylation across Drosophila species. Genome Biol 18:229

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