Periodic Reporting for period 4 - DEPICODE (Decoding the epigenetic signature of memory function in health and disease) Reporting period: 2020-03-01 to 2021-08-31 Summary of the context and overall objectives of the project Our genome is like a library full of books, with the books being the genes. Every cell in our body has the same library but need to read different books to fulfill its function. IN addition, cells need to read new books or close the ones already reads in response to external stimuli. Thus, 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. With reference of our example that the genome is a library and the books are the genes, the epigenetic marks can be viewed as bookmarks in the genome. Key examples of such epigenetic bookmarks are methylation and acetylation of histone-proteins that control the availability of DNA for gene-expression. The addition and removal of these moieties is mediated by the counteracting activity of enzymes that either write or erase these epigenetic marks, the so-called writer and eraser proteins, while epigenetic readers translate the “epigenetic code” into cellular function. In addition, there is increasing evidence that non-coding RNAs control gene-expression and act as key regulators of cellular homeostasis. The role of epigenetic regulation in the adult brain is only emerging but recent evidence suggests that targeting the epigenome could be a suitable novel approach for the treatment of neuropsychiatric and neurodegenerative diseases. A prime example is Alzheimer’s disease which causes a huge emotional and economic burden to our societies and for which no cure is currently available. To better understand the epigenetic underpinnings of brain function in health and disease can help to develop novel approaches for stratified therapies against such devastating diseases. During the course of DEPICODE, we could make substantial progress in this direction. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The aim of the DEPICODE project was to further elucidate the role of epigenetic processes in the healthy and diseased brain with a focus on 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 Alzheimer’s disease 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 regulation cognitive function and that drugs such as JQ1, which are believed to inhibit such reader proteins can ameliorate disease phenotypes in a mouse model for Alzheimer’s disease. In our effort to further elucidate this observation we analyzed mice that lack specific reader proteins from the adult forebrain. Our data shows, however, the effect of JQ1 is unlikely to be mediated via BRD2 or BRD4. Another novel reader protein that we had identified in a proteomic screen as a biding partner for acetylated histone 4 lysine 12 is the Annexin A2 (AnxA2) protein. 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 via the regulation of gene implicated with synaptic plasticity. In conclusion our data supports the view that processes related to histone 4 lysine 12 acetylation and histone-3 lysine 4 tri-methylation are key mediators of memory function and that targeting the corresponding eraser proteins is a suitable therapeutic strategy in cognitive diseases. We could also further elucidate the mechanisms that underlie transgenerational inheritance of cognitive abilities and demonstrated a critical role of non-coding RNAs, namely microRNAs. While these data are fascinating, they also demonstrate that microRNA levels in the periphery can inform about cognitive status, which is one of the reasons why circulating RNAs are discussed as biomarker for brain diseases. In line with this view we could provide further evidence that the analysis of microRNA levels in blood of mice and humans can indicate future cognitive decline and inform about relevant pathomechanisms in the brain. Most of these data have been published in peer-reviewed journals or are in preparation for submission. The data have also been presented at several scientific conferences and to the lay audience in form of talks or media coverage. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) In conclusion DEPICODE has already provided important novel insights to the role of epigenetic gene-expression in the adult brain.