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 HoonManuel Ares, Christopher B. Burge, John Ravits, Frank Rigo, Gene W. Yeo

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

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.

Original languageEnglish
Article number12143
JournalNature Communications
Volume7
DOIs
StatePublished - Jul 5 2016

Bibliographical note

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.

ASJC Scopus subject areas

  • Physics and Astronomy (all)
  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)

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