Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses

Katannya Kapeli, Gabriel A. Pratt, Anthony Q. Vu, Kasey R. Hutt, Fernando J. Martinez, Balaji Sundararaman, Ranjan Batra, Peter Freese, Nicole J. Lambert, Stephanie C. Huelga, Seung J. Chun, Tiffany Y. Liang, Jeremy Chang, John P. Donohue, Lily Shiue, Jiayu Zhang, Haining Zhu, Franca Cambi, Edward Kasarskis, Shawn Hoon, Manuel Ares, Christopher B. Burge, John Ravits, Frank Rigo and Gene W. Yeo ()
Additional contact information
Katannya Kapeli: University of California at San Diego
Gabriel A. Pratt: University of California at San Diego
Anthony Q. Vu: University of California at San Diego
Kasey R. Hutt: University of California at San Diego
Fernando J. Martinez: University of California at San Diego
Balaji Sundararaman: University of California at San Diego
Ranjan Batra: University of California at San Diego
Peter Freese: MIT
Nicole J. Lambert: MIT
Stephanie C. Huelga: University of California at San Diego
Seung J. Chun: Ionis Pharmaceuticals
Tiffany Y. Liang: University of California at San Diego
Jeremy Chang: University of California at San Diego
John P. Donohue: Cell and Developmental Biology, Sinsheimer Labs, University of California
Lily Shiue: Cell and Developmental Biology, Sinsheimer Labs, University of California
Jiayu Zhang: College of Medicine, University of Kentucky
Haining Zhu: College of Medicine, University of Kentucky
Franca Cambi: University of Kentucky
Edward Kasarskis: University of Kentucky
Shawn Hoon: Molecular Engineering Laboratory, A*STAR
Manuel Ares: Cell and Developmental Biology, Sinsheimer Labs, University of California
Christopher B. Burge: MIT
John Ravits: University of California at San Diego
Frank Rigo: Ionis Pharmaceuticals
Gene W. Yeo: University of California at San Diego

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12143

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