Alternative polyadenylation alters protein dosage by switching between intronic and 3′UTR sites

Author:

de Prisco Nicola12ORCID,Ford Caitlin13,Elrod Nathan D.4ORCID,Lee Winston15,Tang Lauren C.6ORCID,Huang Kai-Lieh47ORCID,Lin Ai8ORCID,Ji Ping4ORCID,Jonnakuti Venkata S.9101112,Boyle Lia13ORCID,Cabaj Maximilian1ORCID,Botta Salvatore113,Õunap Katrin1415ORCID,Reinson Karit1415ORCID,Wojcik Monica H.16ORCID,Rosenfeld Jill A.1718ORCID,Bi Weimin1718,Tveten Kristian19ORCID,Prescott Trine19,Gerstner Thorsten20ORCID,Schroeder Audrey21ORCID,Fong Chin-To22,George-Abraham Jaya K.2324ORCID,Buchanan Catherine A.23,Hanson-Khan Andrea2526ORCID,Bernstein Jonathan A.25ORCID,Nella Aikaterini A.10ORCID,Chung Wendy K.327ORCID,Brandt Vicky1ORCID,Jovanovic Marko6,Targoff Kimara L.23,Yalamanchili Hari Krishna1028ORCID,Wagner Eric J.47,Gennarino Vincenzo A.1232930ORCID

Affiliation:

1. Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.

2. Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY, USA.

3. Department of Pediatrics, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

4. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.

5. Department Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA.

6. Department of Biological Sciences, Columbia University, New York, NY, USA.

7. Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

8. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, WC67+HC Dongcheng, Beijing, China.

9. Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA.

10. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA.

11. Program in Quantitative and Computational Biology, Baylor College of Medicine, Houston, TX, USA.

12. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.

13. Department of Translational Medical Science, University of Campania Luigi Vanvitelli, Caserta, Italy.

14. Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.

15. Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

16. Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

18. Baylor Genetics Laboratories, Houston, TX, USA.

19. Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.

20. Department of Child Neurology and Rehabilitation and Department of Pediatrics, Hospital of Southern Norway, Arendal, Norway.

21. Division of Medical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

22. Department of Pediatrics and of Medicine, University of Rochester Medical Center, Rochester, NY, USA.

23. Dell Children’s Medical Group, Austin, TX, USA.

24. Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, USA.

25. Department of Pediatrics, Division of Medical Genetics, Stanford School of Medicine, Palo Alto, CA, USA.

26. Department of Genetics, Stanford School of Medicine, Palo Alto, CA, USA.

27. Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.

28. USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

29. Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

30. Initiative for Columbia Ataxia and Tremor, Columbia University Irving Medical Center, New York, NY, USA.

Abstract

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3′ untranslated region (3′UTR), introns, or exons. Most studies focus on APA within the 3′UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3′UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3′UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3′UTR APA to modulate protein expression.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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