The regulation of neuronal gene expression requires dynamic changes in chromatin structure as evidenced by the fact that dysregulation of the enzymes responsible for chromatin modification often leads to intellectual disability. In this article, we characterize a chromatin-modifying complex containing the X-linked mental retardation-associated protein PHF8 and the Alzheimer’s disease-associated protein TIP60, which regulates the expression of an important neuronal activity-dependent gene, Arc.