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Decoding the epigenetic signature of memory function in health and disease

Periodic Reporting for period 3 - DEPICODE (Decoding the epigenetic signature of memory function in health and disease)

Reporting period: 2018-09-01 to 2020-02-29

Tightly controlled gene expression is a pre-requisite for all cellular processes and an essential determinant of cellular identity. In turn, aberrant gene expression is a hallmark of multifactorial diseases that arise on the background of complex genome-environment interactions. Such genome-environment interactions frequently activate epigenetic mechanisms that add an additional layer of control to the genome and provide cells with a mechanism by which transient stimuli can be transformed into long-term adaptive changes. Key examples of epigenetic modifications are methylation and acetylation. The addition and removal of these moieties is normally mediated by the counteracting activity of enzymes that either write or erase these epigenetic marks, the so-called writer and eraser proteins. In addition, there are epigenetic readers, which then translate the “epigenetic code” into cellular function. The role of epigenetic regulation in the adult brain is only currently emerging but recent evidence suggest that targeting the epigenome could be a suitable novel approach for the treatment of neuropsychiatric and neurodegenerative diseases
The aim of the DEPICODE (Decoding the epigenetic signature of memory function in health and disease) project is to further elucidate the role of epigenetic processes in the adult brain in the context of learning and memory. To this end, we could show that specific eraser proteins play a key role in the pathogenesis of cognitive defects linked to schizophrenia and that histone-methylation writers regulate genetic pathways linked to memory decline as it is observed in the context of Alzheimer’s disease. We also generated evidence to suggest that specific epigenetic reader proteins, namely the BET/BRD proteins, are likely to play a key role in the regulation of cognitive function. Indeed, our data demonstrate that oral administration of a small molecule inhibitor targeting BRD2 and BRD4 ameliorates synaptic plasticity and memory defects in a mouse model for Alzheimer’s disease. In our effort to further elucidate this observation we already generated data suggesting that this effect is unlikely to be mediated via BRD2, since mice lacking BRD2 exhibit memory impairment. Currently, we continue this line of research and are also investigating the specific role of BRD4 in the adult brain. We also study the Anaxin A2 (AmxA2) protein that we identified as a potential reader of the histone 4 lysine 12 acetylation (H4K12ac) mark. In line with previous findings that decreased H4K12ac levels in the adult brain marks the onset of age-associated memory decline we observed that loss of AnxA2 leads to memory impairment. Interestingly AnxA2 appears to regulate genetic pathways associated with H4K12ac-dependent alterative splicing and the extracellular matrix. Both processes are intimately linked to synaptic plasticity. Within DEPICODE we also planned to study the role of epigenetic intergenerational inheritance of acquired phenotypes in the context of memory processes. We could demonstrate that exercise in parents leads to the epigenetic inheritance of a cognitive benefit to their offspring and were able to elucidate the underlying processes.
In conclusion DEPICODE has already provided important novel insights to the role of epigenetic gene-expression in the adult brain.