Role of nucleosome composition and histone variant exchange in associative learning and memory

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Memory formation is a process in which fleeting events produce lasting outcomes by altering gene expression. Mechanisms by which the environment affects genes is not well understood, but it involves epigenetic modifications of histone proteins H2A, H2B, H3, and H4, which regulate access to DNA. My work is focused on understanding how histones regulate access to DNA as a method for understanding how memories form. We recently identified histone variants, which replace existing histones and alter access to DNA, as a novel epigenetic regulator of memory. Specifically, we found that H2A.Z, a variant of histone H2A, is an epigenetic factor that suppress memory through an unknown mechanism. Given its pervasive expression and relevance for memory, we will focus on mechanisms of H2A.Z regulation as an essential step in elucidating the role of histones in mediating lasting changes in behaviour.           H2A.Z has contradictory effects on gene activity and understanding the factors that modify its function is critical for uncovering the basis for its role in memory. Here, we will determine whether Anp32e, a novel regulator of H2A.Z, controls its removal from particular positions to increase gene activity and promote memory. This work will be the first to investigate how histones are regulated at some positions and not others, an essential step in diagraming the mechanism by which histones regulate experience-induced gene activity.           Effects of H2A.Z on gene activity are also influenced by modifying H2A.Z with ubiquitin. How this modification impacts gene activity during learning is not known and proposed studies will elucidate its function in memory. We will focus specifically on ubiquitinated H2A.Z as a filter that modifies how strong a stimulus needs to be to initiate information storage and maintenance as memory. This work will be essential for detangling the complexity of H2A.Z function by identifying the factors that influence when H2A.Z is permissive or restrictive for gene expression, and ultimately, for memory formation.           Finally, we will investigate how H2A.Z integrates with classical mechanisms of memory. Only some cells within a brain region encode a given memory and selecting which cells participate is a competitive process that is positively regulated by memory-promoting genes. Here, we will determine if H2A.Z, a memory suppressor, confers a competitive disadvantage for incorporating cells into memory. This work will provide first insights into epigenetic regulation of cell assemblies and a much needed bridge between epigenetic actions in the nucleus and classical mechanisms of memory.           Overall, this work will produce highly visible research that will advance H2A.Z knowledge across disciplines focused on gene regulation. In particular, this work will transform our understanding of factors that fine-tune gene activity in response to external stimuli to regulate lasting changes in behaviour.