HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
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.
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus  and are accessible through the GEO Series accession numbers GSE131213 (RNA-seq aNSCs), GSE131283 (RNA-seq brain tissues) and GSE131028 (ChIP-seq aNSCs). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org)  via the PRIDE partner repository , with the dataset identifier PXD013730.
RNA-seq of different brain tissue areas of Trrap conditional knockout Mus musculusNCBI Gene Expression Omnibus, GSE131283.
Article and author information
- Zhao-Qi Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal experiments were conducted according to German animal welfare legislation, and the protocol is approved by Thüringen Landesamt für Verbraucherschutz (TLV) (03-042/16), Germany.
- Jeremy J Day, University of Alabama at Birmingham, United States
- Received: July 28, 2020
- Accepted: February 16, 2021
- Accepted Manuscript published: February 17, 2021 (version 1)
- Version of Record published: March 8, 2021 (version 2)
- Version of Record updated: May 18, 2021 (version 3)
- Version of Record updated: July 19, 2021 (version 4)
© 2021, Tapias et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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