The nBAF complex subunit CREST/SS18L1 regulates hippocampal memory processes via tyrosine 397 and histone acetyltransferase CBP

Chromatin modifying/remodeling machinery are important for learning-induced transcriptional activity, yet it remains unclear how they coordinate to drive de novo gene expression for memory formation. Here, we examine the transcription factor known as calcium-responsive transactivator (CREST) in memory formation, synaptic plasticity and learning-induced gene expression. CREST is known to bind major chromatin modifying and remodeling machinery via interaction with CREB-binding protein (CBP) and brahma-related gene 1 (BRG1), respectively. In silico modeling of CREST identified tyrosine 397 (Y397) within the CBP binding domain. Expression of a CREST Y397F point-mutant impairs long-term potentiation and memory. Conversely, expression of a CREST Y397D point-mutant enhances memory in a CBP-dependent manner. Differential gene expression analysis reveals distinct CREST Y397-regulated signatures during memory consolidation. CBP acts through CREB and post-translation modifications to affect memory, but the findings of this study argue for the consideration of the CREST-CBP interaction and Y397 accessibility as factors for memory processes. Overall design: To investigate the contribution of CREST to long-term memory formation, we designed condtions for expressing a phospho-null and -mimetic in the adult dorsal hippocampus. We performed differential gene expression analysis to examine learning-induced gene profiles across 5 distinct conditions consisting of homecage, vehicle and CREST phospho-mutants in 2 different training periods of OLM.