1 PhD project offered in the IPP winter call 2020/2021
Understanding how we learn and store memory is of fundamental interest for basic research, but also carries important translational significance in the context of brain dysregulations, such as mental retardation, cognitive decline with age, and post-traumatic stress disorder. The formation of a new memory includes the crucial phase of memory consolidation, which requires behaviorally induced alterations in the availability of functional mRNAs. We found Gadd45a regulates aversive memory formation by specifically regulating mRNAs coding for synaptic plasticity proteins. The majority of Gadd45a-regulated transcripts contain an extended 3´ untranslated region (3´UTR), which is considered a central hub for post-transcriptional regulation.
In this project, we aim to investigate the mechanisms underlying the regulation of mRNA stability in memory consolidation. We will investigate the physical interaction between Gadd45a and neuronal target RNAs and their consequences for target mRNA/protein localization within the neuron using RNA-immunoprecipitation. We will apply RNA-seq and Omics approaches for analysis of Gadd45a targets, followed by comprehensive bioinformatics analysis of the target RNAs identified. Using neuronal cultures, we will analyze the role of 3’UTR length in synaptic mRNA localization and transport using luciferase-reporter assays. We will test whether the localization of synaptic mRNAs and their encoded proteins are affected in Gadd45a deficient neurons using confocal fluorescence microscopy.
Publications relevant to the project
Arab K, Karaulanov E, Musheev M, Trnka P, Schäfer A., Grummt I, and Niehrs C. (2019). GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat. Genet. 51, 217-223.
Schüle KM, Leichsenring M, Andreani T, Vastolo V, Mallick M, Musheev MU, Karaulanov E, Niehrs C. (2019). GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells. Genes Dev. 33, 782-798