Journal Article

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

Yin, Bo-Kun, Ori, Alessandro, Wang, Zhao-Qi, Krepelova, Anna, Grigaravicius, Paulius, Tapias, Alicia, Lázaro, David, Kelmer Sacramento, Erika, Neri, Francesco, Kirkpatrick, Joanna, Rasa, Seyed Mohammad Mahdi, Koch, Philipp

2021

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Age / Aging / Alzheimer's disease / Animals / Apoptosis / Autism / Brain / Cell cycle / cell lines / Chromosomes and Gene Expression / DNA methylation / Ectopic expression / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Epilepsy / Gene Deletion / Gene expression / Gene Expression Regulation / Histone acetyltransferase / Histone deacetylase / Histones / Homeostasis / Intellectual disabilities / Mice / Mice, Mutant Strains / Microtubules - metabolism / Motor ability / Neurodegeneration / Neurological diseases / Neurons / Neuropathy / Neuroprotection / Neuroscience / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Proteins / Proteomics / Psychosis / Purkinje cells / Purkinje Cells - pathology / Signal Transduction / SP1 / Sp1 protein / Sp1 Transcription Factor - genetics / Sp1 Transcription Factor - metabolism / stathmins / Transcription / Transcriptomics / TRRAP