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| Status |
Public on Mar 02, 2021 |
| Title |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (Transformation/translation domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT and SP1 with microtubule dynamics, in neuroprotection.
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| |
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| Overall design |
Transcriptional and epigenetic landscape of the adult neural stem cells after the deletion of Trrap
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| |
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| Contributor(s) |
Pellon DL, Rasa M, Krepelova A, Neri F, Wang Z |
| Citation(s) |
33594975 |
| |
| Submission date |
May 10, 2019 |
| Last update date |
Mar 04, 2021 |
| Contact name |
Seyed Mohammd Mahdi Rasa |
| E-mail(s) |
SeyedMohammadMahdi.Rasa@uksh.de
|
| Phone |
015258164616
|
| Organization name |
Universitätsklinikum Schleswig-Holstein
|
| Department |
Institut for Immunology
|
| Lab |
Immunology (Prof. Sheffold)
|
| Street address |
Michaelisstrasse 5
|
| City |
Kiel |
| State/province |
Schleswig-Holstein |
| ZIP/Postal code |
24105 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (8)
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| Relations |
| BioProject |
PRJNA542345 |
| SRA |
SRP197587 |
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