Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer's Disease

The immediate early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Here, we show that Arc interacts with dynamic chromatin and closely associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Both these histone modifications, H3K27Ac and H3K9Ac, have recently been shown to be upregulated in late-onset Alzheimer's disease (AD). When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes, which included genes associated with synaptic function, neuronal plasticity, intrinsic excitability, and signalling pathways. Interestingly, about 100 Arc-dependent genes are associated with the pathophysiology of AD. When endogenous Arc expression was induced in HEK293T cells, the transcription of many neuronal genes was increased, suggesting that Arc can control expression in the absence of activated signalling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and suggest that it plays a significant role in the pathophysiology of AD.

Automated summary

The immediate early gene Arc plays a crucial role in regulating synaptic function and memory consolidation. It interacts with dynamic chromatin and associates with histone markers for active enhancers and transcription in cultured rat hippocampal neurons. Upregulated histone modifications associated with late-onset Alzheimer's disease have been found. Altered expression profiles of over 1900 genes, including those involved in synaptic function, neuronal plasticity, excitability, and signaling pathways, were observed when Arc induction was prevented. About 100 Arc-dependent genes are implicated in the pathophysiology of Alzheimer's disease. The induction of endogenous Arc expression in HEK293T cells increased the transcription of neuronal genes, suggesting that Arc can control gene expression independently of activated signaling pathways. These findings establish Arc as a master regulator of activity-dependent gene expression in neurons and suggest its significance in Alzheimer's disease pathophysiology.