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; Gene W. Yeo

doi:10.1038/ncomms12143

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

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115 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 language	English
Article number	12143
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12143
State	Published - 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

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Kapeli, K., Pratt, G. A., Vu, A. Q., Hutt, K. R., Martinez, F. J., Sundararaman, B., Batra, R., Freese, P., Lambert, N. J., Huelga, S. C., Chun, S. J., Liang, T. Y., Chang, J., Donohue, J. P., Shiue, L., Zhang, J., Zhu, H., Cambi, F., Kasarskis, E., ... Yeo, G. W. (2016). Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses. Nature Communications, 7, Article 12143. https://doi.org/10.1038/ncomms12143

@article{7e378184fa904eed8f16827dc6bc164a,

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

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.",

author = "Katannya Kapeli and Pratt, {Gabriel A.} and Vu, {Anthony Q.} and Hutt, {Kasey R.} and Martinez, {Fernando J.} and Balaji Sundararaman and Ranjan Batra and Peter Freese and Lambert, {Nicole J.} and Huelga, {Stephanie C.} and Chun, {Seung J.} and Liang, {Tiffany Y.} and Jeremy Chang and Donohue, {John P.} and Lily Shiue and Jiayu Zhang and Haining Zhu and Franca Cambi and Edward Kasarskis and Shawn Hoon and Manuel Ares and Burge, {Christopher B.} and John Ravits and Frank Rigo and Yeo, {Gene W.}",

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.",

year = "2016",

month = jul,

day = "5",

doi = "10.1038/ncomms12143",

language = "English",

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Kapeli, K, Pratt, GA, Vu, AQ, Hutt, KR, Martinez, FJ, Sundararaman, B, Batra, R, Freese, P, Lambert, NJ, Huelga, SC, Chun, SJ, Liang, TY, Chang, J, Donohue, JP, Shiue, L, Zhang, J, Zhu, H, Cambi, F, Kasarskis, E, Hoon, S, Ares, M, Burge, CB, Ravits, J, Rigo, F & Yeo, GW 2016, 'Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses', Nature Communications, vol. 7, 12143. https://doi.org/10.1038/ncomms12143

TY - JOUR

T1 - Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses

AU - Kapeli, Katannya

AU - Pratt, Gabriel A.

AU - Vu, Anthony Q.

AU - Hutt, Kasey R.

AU - Martinez, Fernando J.

AU - Sundararaman, Balaji

AU - Batra, Ranjan

AU - Freese, Peter

AU - Lambert, Nicole J.

AU - Huelga, Stephanie C.

AU - Chun, Seung J.

AU - Liang, Tiffany Y.

AU - Chang, Jeremy

AU - Donohue, John P.

AU - Shiue, Lily

AU - Zhang, Jiayu

AU - Zhu, Haining

AU - Cambi, Franca

AU - Kasarskis, Edward

AU - Hoon, Shawn

AU - Ares, Manuel

AU - Burge, Christopher B.

AU - Ravits, John

AU - Rigo, Frank

AU - Yeo, Gene W.

N1 - 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.

PY - 2016/7/5

Y1 - 2016/7/5

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms12143

DO - 10.1038/ncomms12143

M3 - Article

C2 - 27378374

AN - SCOPUS:84977518489

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12143

ER -

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

Abstract

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ASJC Scopus subject areas

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