“The role of chromatin readers in memory formation and neurodegeneration”
Alzheimer’s disease (AD) is the most common age associated form of dementia. Yet, the pathology of the disease is to date not well understood on a molecular level. While some cases of AD have a genetic underpinning, the majority of the AD cases (95%) is sporadic. The most realistic approach in the short term is a treatment to delay the onset and thus improve life quality for the affected and cut treatment costs significantly. Notably, it is commonly accepted that late onset AD is a result of variable combination of genetic and environmental risk factors. This puts epigenetic mechanisms in the spotlight for the search for novel treatments, since here environmental factors are translated into molecular alterations. The precise mechanisms how epigenetic processes control memory function are however only beginning to emerge. A finding important for my PHD project is that alterations in histone 4 at lysine 12 actetylation (H4K12ac) were linked to the pathogenesis of Alzheimer’s disease (Peleg et al, 2010). How H4K12ac is regulated during memory formation is however not understood. Moreover, it is completely unclear by which signals neuronal activity is coupled to altered epigenetic gene-expression in the nucleus. In preliminary experiments we performed a proteomic screen using SILAC technology to identify proteins that specifically bind to H4K12ac in neurons. We found a number of proteins that that are known chromatin readers, hence proteins that read the epigenetic code for example by binding to specific epigenetic modifications which initiates subsequent events that control gene-expression. The most interesting proteins were the so called Bromodomain containing proteins (BRD), BRD2 and BRD4. The function of BRD proteins in the adult brain is so far completely unknown but in other cellular systems it has been shown that BRD2 and BRD4 specifically bind to H4K12ac. Further preliminary data shows that pharmacological inhibition of BRD2/4 binding to H4K12ac in the adult hippocampus enhances memory function in mice. The host lab has generated mice that allow the conditional deletion of BRD2 in mice (Brd2 cKO mice) and Brd4 cKO mice will shortly be available. In my PhD thesis I will analyse cognitive function in Brd2/4 cKO mice. To this end I will generate mice that lack Brd2/4 in excitatory or inhibitory neurons of the adult brain and subject these animals to behavior testing including the analysis of memory function (fear conditioning, water maze, T-maze, Y-maze, novel object recognition), anxiety (Elevated plus maze, open field) and sensory motor gating function (pre pulse inhibition of startle response). I will combine the behavior data with a molecular analysis of gene-expression and chromatin plasticity. During my PhD work I want to analyse Brd2/4 levels in AD, study the role of Brd2/4 in memory formation and AD. But also investigate the cellular pathways regulated by Brd2/4 during cognition, as well as the chromatin-distribution of Brd2. And further I want to analyse Brd2-dependent chromatin marks and gene-expression. In conclusion my PhD thesis is based on solid preliminary evidence and will address for the first time to role of chromatin readers in memory formation.
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Java S, Agis-Balboa RC, Cota P, Wittnam J, Gogul-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, KAng H, Farinelli L, Chen W, Fischer A (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328: 753-756