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

Nature communications · 2016 · Vol. 7 · pp. 12143

PubMed DOI PMC Full Text

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

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]

Keywords

[]

MeSH Terms

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

Funding

R01 HG004659 NHGRI NIH HHS (United States)

T32 GM008666 NIGMS NIH HHS (United States)

T32 GM087237 NIGMS NIH HHS (United States)

U54 HG007005 NHGRI NIH HHS (United States)

R01 NS075449 NINDS NIH HHS (United States)

R01 NS077284 NINDS NIH HHS (United States)

I01 BX002149 BLRD VA (United States)

Linked Datasets (6)

GSE77704 GSE via ncbi_elink

GEO

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [RNA-Seq_Stability]

Homo sapiens

36 data files

File	Type	Size
NPC0_ctrl.fastq.gz	RNA-Seq	402.6 MB
NPC0_ctrl.fastq.gz	RNA-Seq	402.6 MB
NPC0_FUS.fastq.gz	RNA-Seq	219.4 MB
NPC0_FUS.fastq.gz	RNA-Seq	219.4 MB
NPC0_TAF15.fastq.gz	RNA-Seq	66.1 MB
NPC0_TAF15.fastq.gz	RNA-Seq	66.1 MB
NPC15_ctrl.fastq.gz	RNA-Seq	1.6 GB
NPC15_ctrl.fastq.gz	RNA-Seq	1.6 GB
NPC15_FUS.fastq.gz	RNA-Seq	361.2 MB
NPC15_FUS.fastq.gz	RNA-Seq	361.2 MB
NPC15_TAF15.fastq.gz	RNA-Seq	157.1 MB
NPC15_TAF15.fastq.gz	RNA-Seq	157.1 MB
NPC1_ctrl.fastq.gz	RNA-Seq	282.1 MB
NPC1_ctrl.fastq.gz	RNA-Seq	282.1 MB
NPC1_FUS.fastq.gz	RNA-Seq	235.2 MB
NPC1_FUS.fastq.gz	RNA-Seq	235.2 MB
NPC1_TAF15.fastq.gz	RNA-Seq	1.3 GB
NPC1_TAF15.fastq.gz	RNA-Seq	1.3 GB
NPC2_ctrl.fastq.gz	RNA-Seq	322.8 MB
NPC2_ctrl.fastq.gz	RNA-Seq	322.8 MB
NPC2_FUS.fastq.gz	RNA-Seq	246.1 MB
NPC2_FUS.fastq.gz	RNA-Seq	246.1 MB
NPC2_TAF15.fastq.gz	RNA-Seq	485.3 MB
NPC2_TAF15.fastq.gz	RNA-Seq	485.3 MB
NPC30_ctrl.fastq.gz	RNA-Seq	442.8 MB
NPC30_ctrl.fastq.gz	RNA-Seq	442.8 MB
NPC30_FUS.fastq.gz	RNA-Seq	251.7 MB
NPC30_FUS.fastq.gz	RNA-Seq	251.7 MB
NPC30_TAF15.fastq.gz	RNA-Seq	181.5 MB
NPC30_TAF15.fastq.gz	RNA-Seq	181.5 MB
NPC4_ctrl.fastq.gz	RNA-Seq	396.3 MB
NPC4_ctrl.fastq.gz	RNA-Seq	396.3 MB
NPC4_FUS.fastq.gz	RNA-Seq	413.6 MB
NPC4_FUS.fastq.gz	RNA-Seq	413.6 MB
NPC4_TAF15.fastq.gz	RNA-Seq	233.8 MB
NPC4_TAF15.fastq.gz	RNA-Seq	233.8 MB

GSE77700 GSE via ncbi_elink

GEO

Distinct and shared molecular targets and functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [CLIP-Seq]

Mus musculus

4 data files

File	Type	Size
TAF15_1.fastq.gz	RIP-Seq	6.0 GB
TAF15_1.fastq.gz	RIP-Seq	6.0 GB
TAF15_2.fastq.gz	RIP-Seq	3.8 GB
TAF15_2.fastq.gz	RIP-Seq	3.8 GB

GSE77703 GSE via ncbi_elink

GEO

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [RNA-Seq_mouse]

Mus musculus

8 data files

File	Type	Size
KK1.fastq.gz	RNA-Seq	942.2 MB
KK1.fastq.gz	RNA-Seq	942.2 MB
KK2.fastq.gz	RNA-Seq	1.1 GB
KK2.fastq.gz	RNA-Seq	1.1 GB
KK7.fastq.gz	RNA-Seq	1.1 GB
KK7.fastq.gz	RNA-Seq	1.1 GB
KK8.fastq.gz	RNA-Seq	1.1 GB
KK8.fastq.gz	RNA-Seq	1.1 GB

GSE77702 GSE via ncbi_elink

GEO

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [RNA-Seq_human]

Homo sapiens

32 data files

File	Type	Size
AV_GY6_2_1_CTGAAGC_L001_R1.fastq.gz	RNA-Seq	395.5 MB
AV_GY6_2_1_CTGAAGC_L001_R1.fastq.gz	RNA-Seq	395.5 MB
AV_GY7_3_1_CGGCTAT_L001_R1.fastq.gz	RNA-Seq	697.7 MB
AV_GY7_3_1_CGGCTAT_L001_R1.fastq.gz	RNA-Seq	697.7 MB
AV_GY7_6_1_TCCGGAG_L005_R1.fastq.gz	RNA-Seq	1011.3 MB
AV_GY7_6_1_TCCGGAG_L005_R1.fastq.gz	RNA-Seq	1011.3 MB
AV_KIN1ALS17_3_1_TAATGCG_L002_R1.fastq.gz	RNA-Seq	737.8 MB
AV_KIN1ALS17_3_1_TAATGCG_L002_R1.fastq.gz	RNA-Seq	737.8 MB
AV_KIN1ALS6_4_1_TCCGCGA_L003_R1.fastq.gz	RNA-Seq	1.0 GB
AV_KIN1ALS6_4_1_TCCGCGA_L003_R1.fastq.gz	RNA-Seq	1.0 GB
AV_KIN1ALS6_4_shSCR_1_CTGAAGC_L004_R1.fastq.gz	RNA-Seq	455.0 MB
AV_KIN1ALS6_4_shSCR_1_CTGAAGC_L004_R1.fastq.gz	RNA-Seq	455.0 MB
FUS_shRNA_1.fastq.gz	RNA-Seq	3.2 GB
FUS_shRNA_1.fastq.gz	RNA-Seq	3.2 GB
FUS_shRNA_2.fastq.gz	RNA-Seq	3.1 GB
FUS_shRNA_2.fastq.gz	RNA-Seq	3.1 GB
FUS_TAF15_shRNA_1.fastq.gz	RNA-Seq	3.2 GB
FUS_TAF15_shRNA_1.fastq.gz	RNA-Seq	3.2 GB
FUS_TAF15_shRNA_2.fastq.gz	RNA-Seq	2.8 GB
FUS_TAF15_shRNA_2.fastq.gz	RNA-Seq	2.8 GB
Scrm_1.fastq.gz	RNA-Seq	1.5 GB
Scrm_1.fastq.gz	RNA-Seq	1.5 GB
Scrm_2.fastq.gz	RNA-Seq	2.2 GB
Scrm_2.fastq.gz	RNA-Seq	2.2 GB
TAF15_shRNA_1.fastq.gz	RNA-Seq	3.1 GB
TAF15_shRNA_1.fastq.gz	RNA-Seq	3.1 GB
TAF15_shRNA_2.fastq.gz	RNA-Seq	2.6 GB
TAF15_shRNA_2.fastq.gz	RNA-Seq	2.6 GB
TDP43_shRNA_1.fastq.gz	RNA-Seq	2.9 GB
TDP43_shRNA_1.fastq.gz	RNA-Seq	2.9 GB
TDP43_shRNA_2.fastq.gz	RNA-Seq	1.9 GB
TDP43_shRNA_2.fastq.gz	RNA-Seq	1.9 GB

GSE77699 GSE via ncbi_elink

GEO

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [array]

Mus musculus

GSE77707 GSE via ncbi_elink

GEO

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses

Mus musculus

Potentially Related Datasets (2)

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

ENCSR827QYL ENCSR ENCODE

RNA Bind-n-Seq (RBNS) pulldown experiment against TAF15

ENCSR936LOF ENCSR ENCODE

RNA Bind-n-Seq (RBNS) pulldown experiment against FUS

Analysis Pipelines (6)

GSE77699 CLIP-seq Data Processing 2 steps

CLIP-seq geo_data_processing GSE77699

GSE77700 CLIP-seq Data Processing 3 steps

CLIP-seq geo_data_processing GSE77700

GSE77702 CLIP-seq Data Processing 5 steps

CLIP-seq geo_data_processing GSE77702

GSE77703 CLIP-seq Data Processing 5 steps

CLIP-seq geo_data_processing GSE77703

GSE77704 CLIP-seq Data Processing 5 steps

CLIP-seq geo_data_processing GSE77704

GSE77707 Microarray Data Processing 2 steps

Microarray geo_data_processing GSE77707