Dataset Information

Trrap-dependent lysine acetylation prevents neurodegeneration by modulating Sp1 transcriptional activity

ABSTRACT: The acetylation levels of histones and other proteins change during aging and have been linked to neurodegeneration. Here we show that deletion of the histone acetyltransferase (HAT) co-factor Trrap specifically impairs the function of the transcription factor Sp1 and the recruitment of HATs to Sp1 target genes. Modulation of Sp1 function by Trrap acts as a hub regulating multiple processes involved in neuron and neural stem cells function and maintenance including microtubule dynamics and the Wnt signaling pathway. Consistently, Trrap conditional mutants exhibit all hallmarks of neurodegeneration including dendrite retraction and axonal swellings, neuron death, astrogliosis, microglia activation, demyelination and decreased adult neurogenesis. Our results uncovered a novel functional network, essential to prevent neurodegeneration, and involving the specific regulation of Sp1 transcription factor by Trrap-HAT.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Joanna Kirkpatrick

LAB HEAD: Zhao-Qi Wang

PROVIDER: PXD013730 | Pride | 2021-03-02

REPOSITORIES: Pride

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Publications

HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration.

Tapias Alicia A Lázaro David D Yin Bo-Kun BK Rasa Seyed Mohammad Mahdi SMM Krepelova Anna A Kelmer Sacramento Erika E Grigaravicius Paulius P Koch Philipp P Kirkpatrick Joanna J Ori Alessandro A Neri Francesco F Wang Zhao-Qi ZQ

eLife 20210217

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 ...[more]

PMID: 33594975

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Project description:Sp1 is a transcription factor able to regulate many genes through its DNA binding domain, containing three zinc fingers. We were interested in identifying target genes regulated by Sp1, with a special emphasis to those involved in proliferation and cancer. Our approach was to treat HeLa cells with a siRNA directed against Sp1 mRNA (siSp1) to decrease the expression of Sp1 and, in turn, the genes activated by this transcription factor. Sp1 siRNA treatment led to a great number of differentially expressed genes as determined by whole genome cDNA microarray analysis. Underexpressed genes were selected since they represent putative genes activated by Sp1. These underexpressed genes were classified in six Gene Onthology categories, namely proliferation and cancer, mRNA processing, lipidic metabolism, glucidic metabolism, transcription and translation. Putative Sp1 binding sites were found in the promoters of the selected genes using the MatchTM software. After literature mining, 11 genes were selected for further validation of their expression levels using RT-real time PCR. Underexpression was confirmed for the 11 genes plus Sp1 in HeLa cells after siSp1 treatment. Additionally, EMSA and chromatin immunoprecipitation assays were performed to test for binding between Sp1 and the promoters of these genes. We observed binding of Sp1 to the promoters of RAB20, FGF21, IHPK2, ARHGAP18, NPM3, SRSF7, CALM3, PGD and Sp1 itself. Finally, the mRNA levels of RAB20, FGF21 and IHPK2, three genes related with proliferation and cancer, were determined after overexpression of Sp1 in HeLa cells, to confirm their relationship with Sp1. The aim of our study was to evaluate, by using whole genome microarrays, the effects of a siRNA against the transcription factor of Sp1 in HeLa cells. Using this methodology genes activated by Sp1 could be downregulated. The obtective was to determine new genes regulated at the cellular level. Triplicate samples were hybridized for each experimental condition (6 samples in total). The samples provided were analyzed using the specific software GeneSpring GX.

Dataset Information

Trrap-dependent lysine acetylation prevents neurodegeneration by modulating Sp1 transcriptional activity

Publications

HAT cofactor TRRAP modulates microtubule dynamics via SP1 signaling to prevent neurodegeneration.

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