Navigating memory and neuron identity with the COMPASS complexes

Abstract

Epigenetic post-translation modifications are thought to be involved in the maintenance of postmitotic neuron subtypes, however, their role in maintaining differentiated cell-type specific identities is not clear. Previous findings in human, mouse, and Drosophila, indicate that the COMPASS family of methyltransferases may be required for post-mitotic neuron function. Using the model organism Drosophila melanogaster, I explored the COMPASS methyltransferases trx, trr, and Set1 for a function in the mushroom body (MB), the memory centre of the fly brain. trx deficient MB neurons retained normal training gene activation, however, they had reduced capacity for translation, a process that is acutely required for long-term memory (LTM), but dispensable for short-term memory (STM). To understand how trx promotes LTM and translation, I used a combination of MB-specific ChIP-, ATAC- and RNA-sequencing to identify trx target genes. I show that trx is required to maintain expression of several novel MB-enriched genes; genes highly expressed in the MB compared to the surrounding tissue of the whole head. Several of these MB-enriched genes are required in the MB for LTM, including the nuclear receptor Hr51, and lactate dehydrogenase (Ldh), an enzyme responsible for interconverting lactate and pyruvate. I present preliminary data that suggests trx may work cooperatively with Hr51 to activate Ldh and additional translational genes in the MB. I also show that Ldh is required in the MB for normal translation capacity, and both trx and Ldh support a pool of lactate in MBgamma neurons. Taken together, these data suggest that trx maintains a metabolic state in MBgamma neurons that enables a high capacity for protein translation, a process that is essential for LTM. Targets of trr and Set1 were also identified, including potential MB identity genes. Interestingly, Set1 may help regulate transposable element expression in the MB, a process that is required in the mammalian hippocampus for memory. These findings provide new insight into the function of COMPASS methyltransferases in fully differentiated neurons, and in memory formation via translational control.