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

Chromatin-modifying and -remodeling machineries 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 machineries 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 consideration of the CREST-CBP interaction and Y397 accessibility as factors in memory processes.