Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs.
Clotilde Lagier-Tourenne, Magdalini Polymenidou, Kasey R Hutt, Anthony Q Vu, Michael Baughn, Stephanie C Huelga, Kevin M Clutario, Shuo-Chien Ling, Tiffany Y Liang, Curt Mazur, Edward Wancewicz, Aneeza S Kim, Andy Watt, Sue Freier, Geoffrey G Hicks, John Paul Donohue, Lily Shiue, C Frank Bennett, John Ravits, Don W Cleveland, Gene W Yeo
Nature neuroscience · 2012 · Vol. 15 (11) · pp. 1488-97
Abstract
FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.
Linked datasets 4
Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs
Mus musculus
Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (RNA-Seq)
Mus musculus
36 data files
| File | Type | Size |
|---|---|---|
| MP27_1.fastq | RNA-Seq | 700.9 MB |
| MP27_3.fastq | RNA-Seq | 817.9 MB |
| MP28_1.fastq | RNA-Seq | 781.1 MB |
| MP28_2.fastq | RNA-Seq | 772.0 MB |
| MP32_1.fastq | RNA-Seq | 950.4 MB |
| MP32_2.fastq | RNA-Seq | 809.8 MB |
| MP33_1.fastq | RNA-Seq | 794.7 MB |
| SRR556767 | RNA-Seq | 758.1 MB |
| SRR556767_GSM998876 | RNA-Seq | 758.0 MB |
| SRR556768 | RNA-Seq | 905.8 MB |
| SRR556768_GSM998877 | RNA-Seq | 905.0 MB |
| SRR556769 | RNA-Seq | 845.6 MB |
| SRR556769_GSM998878 | RNA-Seq | 845.0 MB |
| SRR556770 | RNA-Seq | 1009.5 MB |
| SRR556770_GSM998879 | RNA-Seq | 1009.0 MB |
| SRR556771 | RNA-Seq | 1011.7 MB |
| SRR556771_GSM998880 | RNA-Seq | 1011.0 MB |
| SRR556772_GSM998881 | RNA-Seq | 700.0 MB |
| SRR556773 | RNA-Seq | 819.7 MB |
| SRR556773_GSM998882 | RNA-Seq | 819.0 MB |
| SRR556774_GSM998883 | RNA-Seq | 817.0 MB |
| SRR556775_GSM998884 | RNA-Seq | 781.0 MB |
| SRR556776_GSM998885 | RNA-Seq | 772.0 MB |
| SRR556777 | RNA-Seq | 993.2 MB |
| SRR556777_GSM998886 | RNA-Seq | 993.0 MB |
| SRR556778 | RNA-Seq | 1019.7 MB |
| SRR556778_GSM998887 | RNA-Seq | 1019.0 MB |
| SRR556779 | RNA-Seq | 1010.6 MB |
| SRR556779_GSM998888 | RNA-Seq | 1010.0 MB |
| SRR556780_GSM998889 | RNA-Seq | 950.0 MB |
| SRR556781_GSM998890 | RNA-Seq | 809.0 MB |
| SRR556782_GSM998891 | RNA-Seq | 794.0 MB |
| SRR556783 | RNA-Seq | 1.0 GB |
| SRR556783_GSM998892 | RNA-Seq | 1.0 GB |
| SRR556784 | RNA-Seq | 725.7 MB |
| SRR556784_GSM998893 | RNA-Seq | 725.0 MB |
Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (CLIP-Seq)
Mus musculus
10 data files
| File | Type | Size |
|---|---|---|
| MP43.fastq | RNA-Seq | 2.8 GB |
| MP45.fastq | RNA-Seq | 3.2 GB |
| SRR556762 | RNA-Seq | 1.6 GB |
| SRR556762_GSM998871 | RNA-Seq | 1.6 GB |
| SRR556763_GSM998872 | RNA-Seq | 2.8 GB |
| SRR556764 | RNA-Seq | 3.3 GB |
| SRR556764_GSM998873 | RNA-Seq | 3.3 GB |
| SRR556765_GSM998874 | RNA-Seq | 3.2 GB |
| SRR556766 | RNA-Seq | 3.1 GB |
| SRR556766_GSM998875 | RNA-Seq | 3.1 GB |
Analysis pipelines 4
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE40649 Microarray Data Processing geo_data_processing | Microarray | 2 | GSE40649 |
| GSE40651 CLIP-seq Data Processing geo_data_processing | CLIP-seq | 1 | GSE40651 |
| GSE40652 RNA-seq Data Processing geo_data_processing | RNA-seq | 1 | GSE40652 |
| GSE40653 Microarray Data Processing geo_data_processing | Microarray | 2 | GSE40653 |
Funding 12 grants
| Grant | Funder |
|---|---|
| R01 HG004659 | NHGRI NIH HHS (United States) |
| R01 NS075449 | NINDS NIH HHS (United States) |
| R01 NS027036 | NINDS NIH HHS (United States) |
| HG004659 | NHGRI NIH HHS (United States) |
| R01 GM084317 | NIGMS NIH HHS (United States) |
| 089701 | Wellcome Trust (United Kingdom) |
| R01NS075449 | NINDS NIH HHS (United States) |
| GM084317 | NIGMS NIH HHS (United States) |
| K99 NS075216 | NINDS NIH HHS (United States) |
| K99NS075216 | NINDS NIH HHS (United States) |
| R37NS27036 | NINDS NIH HHS (United States) |
| R37 NS027036 | NINDS NIH HHS (United States) |