Role for Chromatin Remodeling Factor Chd1 in Learning and Memory

Abstract

Precise temporal and spatial regulation of gene expression in the brain is a prerequisite for cognitive processes such as learning and memory. Epigenetic mechanisms that modulate the chromatin structure have emerged as important regulators in this context. While posttranslational modification of histones or the modification of DNA bases have been examined in detail in many studies, the role of ATP-dependent chromatin remodeling factors (ChRFs) in learning- and memory-associated gene regulation has largely remained obscure. Here we present data that implicate the highly conserved chromatin assembly and remodeling factor Chd1 in memory formation and the control of immediate early gene (IEG) response in the hippocampus. We used various paradigms to assess short-and long-term memory in mice bearing a mutated <i>Chd1</i> gene that gives rise to an N-terminally truncated protein. Our data demonstrate that the <i>Chd1</i> mutation negatively affects long-term object recognition and short- and long-term spatial memory. We found that Chd1 regulates hippocampal expression of the IEG <i>early growth response 1</i> (<i>Egr1</i>) and <i>activity-regulated cytoskeleton-associated</i> (<i>Arc</i>) but not <i>cFos</i> and <i>brain derived neurotrophic factor</i> (<i>Bdnf</i>), because the <i>Chd1</i>-mutation led to dysregulation of <i>Egr1</i> and <i>Arc</i> expression in naive mice and in mice analyzed at different stages of object location memory (OLM) testing. Of note, Chd1 likely regulates <i>Egr1</i> in a direct manner, because chromatin immunoprecipitation (ChIP) assays revealed enrichment of Chd1 upon stimulation at the <i>Egr1</i> genomic locus in the hippocampus and in cultured cells. Together these data support a role for Chd1 as a critical regulator of molecular mechanisms governing memory-related processes, and they show that this function involves the N-terminal serine-rich region of the protein.