The TRRAP-HAT-Sp1 axis maintains brain homeostasis

The homeostasis of the brain is tightly controlled by the viability and functionality of various cell types, including neurons and glial cells, like oligodendrocytes, astrocytes as well as microglia. Defects of neurogenesis and maintenance of neural cells are associated with multiple neuropathologies, such as Intellectual Disability (ID) and Autism Spectrum Disorders (ASD) among other diseases. HAT and HDAC modulate brain functionality, e.g. memory formation, cognitive function, and neuroprotection, whereas the disturbance of the acetylation profiles has been related to multiple neuropathological diseases. However, how epigenetic regulation participates in the neurodevelopmental, neural differentiation and neurodegenerative processes remains largely unknown. In our studies, we have chosen the HAT adaptor, Trrap, to investigate how the disturbance of acetylation would affect brain functionality. We show that Trrap deletion in post-mitotic neurons results in neurodegeneration. In addition, Trrap deficiency in adult neural stem cells compromises their self-renewal and differentiation. With integrated transcriptomics, epigenomics, and proteomics we identify Sp1 as the master regulator controlled by Trrap-HAT and demonstrate that the Trrap-HAT-Sp1 axis ensures the proper expression of genes involved in microtubule dynamics. We find that Trrap mediates Sp1 binding through the maintenance of the acetylation profile on Sp1 and that acetylation of Sp1 plays an important role, dependent and independent of Trrap, in its transcription activation. Taken together, we demonstrate that Trrap, through its mediated acetylation, is involved in neuroprotection and neural differentiation via the regulation of Sp1 activity. My dissertation provides a novel insight into the role of epigenetic regulation of transcription factors in the maintenance of brain homeostasis and preventing neurodegeneration.