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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
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
Duan, Hong; de Navas, Luis F; Hu, Fuqu et al. (2018) The mir-279/996 cluster represses receptor tyrosine kinase signaling to determine cell fates in the Drosophila eye. Development 145:
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:
Mohammed, Jaaved; Flynt, Alex S; Panzarino, Alexandra M et al. (2018) Deep experimental profiling of microRNA diversity, deployment, and evolution across the Drosophila genus. Genome Res 28:52-65
Lin, Ching-Jung; Hu, Fuqu; Dubruille, Raphaelle et al. (2018) The hpRNA/RNAi Pathway Is Essential to Resolve Intragenomic Conflict in the Drosophila Male Germline. Dev Cell 46:316-326.e5
Yao, Liqun; Wang, Shenqiu; Westholm, Jakub O et al. (2017) Genome-wide identification of Grainy head targets in Drosophila reveals regulatory interactions with the POU domain transcription factor Vvl. Development 144:3145-3155
Kan, Lijuan; Grozhik, Anya V; Vedanayagam, Jeffrey et al. (2017) The m6A pathway facilitates sex determination in Drosophila. Nat Commun 8:15737
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

Showing the most recent 10 out of 28 publications