ERC Consolidator grant DEPICODE
(Decoding the epigenetic signature of memory function in health and disease)
Summary
Aberrant gene expression is also a hallmark of multifactorial diseases that arises 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. The term epigenetics was originally coined by Conrad Waddington to describe changes of a phenotype that do not depend on altered DNA-sequence. Nowadays, it is often more generally used to refer to the processes regulated via the ‘epigenetic machinery’ that mediates modifications of DNA, histone proteins which are involved in forming chromatin and also refer to the action of non-coding RNAs.
The emerging field of neuroepigenetics investigates such processes in the context of neuronal plasticity, memory function and brain diseases. My group has significantly contributed to this novel research field. It is however fair to say that the role of “epigenetics” in memory function is still met with some scepticism in the neurosciences, which is in part due to the fact that many of the current studies have been describing phenomena and mechanistic data to explain how epigenetic processes control memory function in health and disease are comparatively sparse. The major objective of DEPICODE is to address this issue and help to consolidate the field of neuroepigenetics by providing insight to the mechanisms by which epigenetic processes contribute to memory formation under physiological and pathological conditions.
Main achievements
We could substantialize our central hypothesis that variable combinations of genetic and environmental factors lead to epigenetic changes in the central nervous system and thus represent suitable drugs targets 1,2,3. We could also further elucidate the machinery that orchestrates epigenetic processes in the brain and demonstrated for example that pharmacological inhibition of the BRD histone-reader proteins ameliorated memory impairment in a mouse model for Alzheimer’s disease (AD)4. More recent findings demonstrate that this effect is not due to the inhibition of BRD2 (manuscript in preparation). While BRD proteins are known to “read” specific histone-modifications, we also studied the ANXA2 protein and could show that it is linked to histone-mediated gene-expression control. Reduced levels of ANXA2 can improve memory function in mice (manuscript in preparation). A key role in cognitive function has also been suggested for the machinery that controls histone 3 methylation and we could demonstrate that the different enzymes of this family distinctly affect neuronal gene-expression and memory function 56. Part of the DEPICODE project was also to study if and how epigenetic processes affect transgenerational inheritance of cognitive function. Here we realized that instead of histone-based processes the role of non-coding RNA seems to play a central role. Thus, employing mice as model systems our data shows that exercise can improve memory consolidation in the offspring. This effect was mechanistically linked to altered microRNA expression in germ cells 7. Further research based on these findings suggest that the analysis of non-coding RNAs in liquid biopsies can inform about cognitive status in mice and humans and may help to develop stratified RNA therapies for dementia 89.
Our research on the role of histone-modifications helped to enabled a clinical trial in which Ad patients are treated with an FDA approved drug that acts as a histone-deacetylase inhibitor (https://clinicaltrials.gov/ct2/show/NCT03056495). Another interdisciplinary development is our collaborative work with neurodevelopmental researchers. We could for example show that inhibition of histone-acetylation can induced gyration of the mouse cortex, a process that is normally specific to humans10. This allows us now to explore the differences and commonalities of epigenetic processes in neurodevelopmental and adult-onset cognitive diseases and help for example to establish a novel ERA-NET Neuron project. Furthermore, our on non-coding RNAs in transgenerational effects linked to cognition support the idea that the analysis of such RNAs in circulation can inform about cognitive status. One hypothesis is that RNAs are synaptically released. To better understand the interplay of RNA in the brain and the circulation we started to profile the synaptic RNAome and developed for example a novel microfluids chamber that allows the specific measurement of synaptic RNAs via next generation sequencing approaches 11.
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- Islam, M. R. et al. Epigenetic gene expression links heart failure to memory impairment. Embo Mol Med13, Epub ahed of print (2021).
- Benito, E. et al. The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice. Transl Psychiatry.7, e1239 (2017).
- Kerimoglu, C. et al. KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions. Cell reports20, 538-548 (2017).
- Michurina, A. et al. Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron-enriched genes. EMBO Jepub ahead of print (2021).
- Benito E et al. RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment. Cell reports 23:546-554 (2018).
- Goldberg, M. et al. Exercise as a model to identify microRNAs linked to human cognition: A role for microRNA-409 and microRNA-501. Translational Psychiatry11, 514 (2021).
- Islam, M., R. et al. A microRNA-signature that correlates with cognition and is a target against cognitive decline. EMBO Mol Meddoi: 10.15252/emmm.202013659. Online ahead of print. (2021).
- Kerimoglu, C. et al. H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression. Science Advancesepub ahead of print, doi:10.1101/2021.03.06.434209 (2021).
- Epple, R. et al. The Coding and Small Non-coding Hippocampal Synaptic RNAome. Mol Neurobiol.58, 2940-2953 (2021).