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 Jr; 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

Nat Commun. 2016 Jul 5:7:12143. doi: 10.1038/ncomms12143.

Authors

Katannya Kapeli^{1

2

3}, Gabriel A Pratt^{1

2

4}, Anthony Q Vu^{1

2}, Kasey R Hutt^{1

2}, Fernando J Martinez^{1

2}, Balaji Sundararaman^{1

2}, Ranjan Batra^{1

2

5}, Peter Freese⁶, Nicole J Lambert⁶, Stephanie C Huelga^{1

2

4}, Seung J Chun⁷, Tiffany Y Liang^{1

2}, Jeremy Chang^{1

2}, John P Donohue⁸, Lily Shiue⁸, Jiayu Zhang⁹, Haining Zhu⁹, Franca Cambi¹⁰, Edward Kasarskis¹⁰, Shawn Hoon¹¹, Manuel Ares Jr⁸, Christopher B Burge⁶, John Ravits⁵, Frank Rigo⁷, Gene W Yeo^{1

2

3

4

11}

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
² Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA.
³ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
⁴ Department of Bioinformatics and Systems Biology, University of California at San Diego, La Jolla, California 92093, USA.
⁵ Department of Neurosciences, University of California at San Diego, La Jolla, California 92093, USA.
⁶ Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
⁷ Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
⁸ Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California 95064, USA.
⁹ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
¹⁰ Department of Neurology, University of Kentucky, Lexington, Kentucky 40536, USA.
¹¹ Molecular Engineering Laboratory, A*STAR, Singapore 138673, Singapore.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Alternative Splicing / genetics*
Amyotrophic Lateral Sclerosis / genetics*
Animals
Computational Biology / methods
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Disease Models, Animal
Female
Fibroblasts
Gene Knockdown Techniques
High-Throughput Nucleotide Sequencing / methods
Humans
Induced Pluripotent Stem Cells
Introns / genetics
Mice
Mice, Inbred C57BL
Motor Neurons / metabolism
Mutation
Oligonucleotides, Antisense / administration & dosage
Oligonucleotides, Antisense / genetics
Primary Cell Culture
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
RNA-Binding Protein FUS / genetics*
RNA-Binding Protein FUS / metabolism
Sequence Analysis, RNA / methods
TATA-Binding Protein Associated Factors / genetics*
TATA-Binding Protein Associated Factors / metabolism

Substances

3' Untranslated Regions
DNA-Binding Proteins
FUS protein, human
FUS protein, mouse
Oligonucleotides, Antisense
RNA, Messenger
RNA, Small Interfering
RNA-Binding Protein FUS
TAF15 protein, human
TAF15 protein, mouse
TARDBP protein, human
TATA-Binding Protein Associated Factors
TDP-43 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding