HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
- Leibniz Institute on Ageing - Fritz Lipmann Institute, Germany
- Leibniz Institute on Aging - Fritz Lipmann Institute, Germany
Abstract
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.
Data availability
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus [80] 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) [81] via the PRIDE partner repository [82], with the dataset identifier PXD013730.
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RNA-seq of different brain tissue areas of Trrap conditional knockout Mus musculusNCBI Gene Expression Omnibus, GSE131283.
Article and author information
Author details
Seyed Mohammad Mahdi Rasa
Funding
Leibniz Publik
- Zhao-Qi Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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.
Copyright
© 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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HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration
eLife 10:e61531.
https://doi.org/10.7554/eLife.61531
Further reading
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- Chromosomes and Gene Expression
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Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
