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 co...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
eLife Sciences Publications Ltd
2021-02-01
|
Series: | eLife |
Subjects: | |
Online Access: | https://elifesciences.org/articles/61531 |
id |
doaj-33e304c7257749b2a06dea0c9d2f2260 |
---|---|
record_format |
Article |
spelling |
doaj-33e304c7257749b2a06dea0c9d2f22602021-07-19T11:51:45ZengeLife Sciences Publications LtdeLife2050-084X2021-02-011010.7554/eLife.61531HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegenerationAlicia Tapias0David Lázaro1Bo-Kun Yin2Seyed Mohammad Mahdi Rasa3https://orcid.org/0000-0001-6850-8909Anna Krepelova4Erika Kelmer Sacramento5Paulius Grigaravicius6Philipp Koch7https://orcid.org/0000-0003-2825-7943Joanna Kirkpatrick8Alessandro Ori9https://orcid.org/0000-0002-3046-0871Francesco Neri10Zhao-Qi Wang11https://orcid.org/0000-0002-8336-3485Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, GermanyLeibniz Institute on Aging – Fritz Lipmann Institute (FLI), Jena, Germany; Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Jena, GermanyBrain 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/transcription 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.https://elifesciences.org/articles/61531cell linesTRRAPSP1Brainstathmins |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alicia Tapias David Lázaro Bo-Kun Yin Seyed Mohammad Mahdi Rasa Anna Krepelova Erika Kelmer Sacramento Paulius Grigaravicius Philipp Koch Joanna Kirkpatrick Alessandro Ori Francesco Neri Zhao-Qi Wang |
spellingShingle |
Alicia Tapias David Lázaro Bo-Kun Yin Seyed Mohammad Mahdi Rasa Anna Krepelova Erika Kelmer Sacramento Paulius Grigaravicius Philipp Koch Joanna Kirkpatrick Alessandro Ori Francesco Neri Zhao-Qi Wang HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration eLife cell lines TRRAP SP1 Brain stathmins |
author_facet |
Alicia Tapias David Lázaro Bo-Kun Yin Seyed Mohammad Mahdi Rasa Anna Krepelova Erika Kelmer Sacramento Paulius Grigaravicius Philipp Koch Joanna Kirkpatrick Alessandro Ori Francesco Neri Zhao-Qi Wang |
author_sort |
Alicia Tapias |
title |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
title_short |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
title_full |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
title_fullStr |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
title_full_unstemmed |
HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration |
title_sort |
hat cofactor trrap modulates microtubule dynamics via sp1 signaling to prevent neurodegeneration |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2021-02-01 |
description |
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/transcription 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. |
topic |
cell lines TRRAP SP1 Brain stathmins |
url |
https://elifesciences.org/articles/61531 |
work_keys_str_mv |
AT aliciatapias hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT davidlazaro hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT bokunyin hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT seyedmohammadmahdirasa hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT annakrepelova hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT erikakelmersacramento hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT pauliusgrigaravicius hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT philippkoch hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT joannakirkpatrick hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT alessandroori hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT francesconeri hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration AT zhaoqiwang hatcofactortrrapmodulatesmicrotubuledynamicsviasp1signalingtopreventneurodegeneration |
_version_ |
1721294963040321536 |