Distinct and Shared Functions of ALS-Associated Proteins TDP-43, FUS and TAF15 Revealed by Multisystem Analyses

Authors

Katannya Kapeli, University of California - San Diego
Gabriel A. Pratt, University of California - San Diego
Anthony Q. Vu, University of California - San Diego
Kasey R. Hutt, University of California - San Diego
Fernando J. Martinez, University of California - San Diego
Balaji Sundararaman, University of California - San Diego
Ranjan Batra, University of California - San Diego
Peter Freese, Massachusetts Institute of Technology
Nicole J. Lambert, Massachusetts Institute of Technology
Stephanie C. Huelga, University of California - San Diego
Seung J. Chun, Ionis Pharmaceuticals
Tiffany Y. Liang, University of California - San Diego
Jeremy Chang, University of California - San Diego
John P. Donohue, University of California - Santa Cruz
Lily Shiue, University of California - Santa Cruz
Jiayu Zhang, University of KentuckyFollow
Haining Zhu, University of KentuckyFollow
Franca Cambi, University of KentuckyFollow
Edward J. Kasarskis, University of KentuckyFollow
Shawn Hoon, A*STAR, Singapore
Manuel Ares Jr., University of California - Santa Cruz
Christopher B. Burge, Massachusetts Institute of Technology
John Ravits, University of California - San Diego
Frank Rigo, Ionis Pharmaceuticals
Gene W. Yeo, University of California - San Diego

Abstract

The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3′ untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism.

Document Type

Article

Publication Date

7-5-2016

Notes/Citation Information

Published in Nature Communications, v. 7, article no. 12143, p. 1-14.

© The Author(s) 2016

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Digital Object Identifier (DOI)

https://doi.org/10.1038/ncomms12143

Funding Information

S.C.H. and G.A.P. were funded by National Science Foundation Graduate Research Fellowships. G.A.P. was also partially supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM008666. This work was supported by grants from the National Institutes of Health (HG004659, NS075449 and HG007005 to G.W.Y; NS077284 to H.Z.), the California Institute of Regenerative Medicine (RB3-05009 and RB4-06045 to G.W.Y.) and ALS Association (VC8K27 to G.W.Y.; 6SE340 to H.Z.). This work was partially supported by NIH grant HG007005 to C.B.B.

Related Content

The accession number for the sequencing data deposited in GEO for this paper is GSE77707.

Repository Citation

Kapeli, Katannya; Pratt, Gabriel A.; Vu, Anthony Q.; Hutt, Kasey R.; Martinez, Fernando J.; Sundararaman, Balaji; Batra, Ranjan; Freese, Peter; Lambert, Nicole J.; Huelga, Stephanie C.; Chun, Seung J.; Liang, Tiffany Y.; Chang, Jeremy; Donohue, John P.; Shiue, Lily; Zhang, Jiayu; Zhu, Haining; Cambi, Franca; Kasarskis, Edward J.; Hoon, Shawn; Ares, Manuel Jr.; Burge, Christopher B.; Ravits, John; Rigo, Frank; and Yeo, Gene W., "Distinct and Shared Functions of ALS-Associated Proteins TDP-43, FUS and TAF15 Revealed by Multisystem Analyses" (2016). Molecular and Cellular Biochemistry Faculty Publications. 95.
https://uknowledge.uky.edu/biochem_facpub/95