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

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.

CRISPR single base editing, neuronal disease modelling and functional genomics for genetic variant analysis: pipeline validation using Kleefstra syndrome EHMT1 haploinsufficiency

“…In rodents, EGR1 (Early growth response 1) co-localizes with Nestin expression and is a marker of NPCs [ 45 ]. SP1 regulates cell cycle, and in concert with E2F3 controls cell cycle transcription networks and epigenetic modifiers that determines cell fate [ 46 , 47 ]. SP2 is a regulator of late neurogenic gene expression [ 48 ].…”

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

“…TRRAP is the standard component of many histone acetyltransferase complexes that are involved in the chromatin modification during the transcription, duplication, and repair of DNA [ 53 ]. TRRAP modulates gene transcription by regulating key transcription factors, such as E2F1, c-Myc, p53, and Sp1 [ 54 , 55 ]. Trrap -knockout mice were lethal [ 56 ].…”

“…Trrap -knockout mice were lethal [ 56 ]. Deleting Trrap in Purkinje neurons affected microtubule dynamics, resulting in neurodegeneration in old mice [ 54 ]. Notably, rare TRRAP mutations were found in some patients with schizophrenia [ 57 ], ID, and ASD [ 58 , 59 , 60 ].…”

TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis

“…Using mouse models, we previously showed that Trrap deletion causes premature differentiation of embryonic neuroprogenitors (NPCs) by disrupting their cell cycle progression during neocortical neurogenesis [43] . While dissecting Trrap function in post-mitotic neurons, we demonstrated that Trrap is not required for development of Purkinje cells in the cerebellum, but prevents their degeneration in adult life [48] . These studies demonstrate the involvement of Trrap in the maintenance of embryonic neurogenesis and post-mitotic neurons.…”

“…These studies demonstrate the involvement of Trrap in the maintenance of embryonic neurogenesis and post-mitotic neurons. Molecularly, Trrap recruits Sp1 to chromatin and facilitates the Sp1 binding to the promoters of microtubule-destabilizing phosphoproteins STMN3 and STMN4 (STMN3/4) to maintain proper microtubule dynamics in neurons [48] . This study suggests that Trrap and/or HAT is required for Sp1 transcriptional activity.…”