Deciphering the cell type-specific gene regulatory network of learning
Final Report Abstract
1. We were able to establish important aspects of the role of epigenetic modifications in memory formation by studying time-dependent DNA methylation and histone modifications in both neuronal and non-neuronal cells in the hippocampus and anterior cingulate cortex in response to contextual fear conditioning (CFC). In particular we found that gene and CRM specific DNA methylation in neurons associated with memory formation is region-specific and seems to play a dual role during consolidation and maintenance of memory. On the other hand, histone modifications showed global rather than region-specific changes that are likely to be restricted to memory consolidation. Decoupling from IE gene expression indicates that histone modification may provide the cellular correlate of attention, whereas DNA methylation may provide the mnemonic substrate to memory. Interestingly, also non-neuronal cells show a response to CFC, which led us to suspect that they may be implicated in memory formation. The role of non-neuronal cells in memory formation may be a topic of future investigations into the field of the epigenetics of memory formation. 2. In a follow-up study we investigated the spatial-temporal changes of hydroxymethyl cytosine (5hmC) levels in CA1, ACC and non-neuronal cells in response to CFC. 5hmC is highly enriched in the brain, and in particular in the hippocampus, cortex and cerebellum. With this study we were able to corroborate that 5hmC may be an epigenetic marker implicated in memory formation (rather than just a degradation product of 5mC) and maintenance. Most strikingly, the spatial-temporal pattern of methylation and hydroxy-methylation in the CA1 neurons were found to be complementary: whereas methylation occurs 1h after CS exposure and is absent after a time period of weeks, hydroxy-methylation follows the opposite pattern. One explanation for this may be a 5hmC implication in priming the neuron for a facilitated response to inputs subsequent to the CS event, in line with the general observation that hydroxymethylation correlates with activated gene expression. In the ACC region, 5hmC and 5mC levels have similar spatial-temporal patterns, with increased levels over 4 weeks, indicating that 5hmC may exert a function in memory maintenance. Interestingly, also non-neuronal cells respond to CS with changes in hydroxymethylation, indicating their possible role in synaptic reorganization upon memory formation and maintenance. 3. We developed the web applications OASIS and OASIS2 for the analysis of sRNA-seq data. OASIS performs alignment and annotation of sRNA species, predicts novel miRNAs for non-matching sRNAs, performs multivariate differential expression analysis and detects sRNA biomarker signatures. OASIS2 is an update of OASIS which, in addition to improving precision and speed of its features, includes a module for the recognition of viral, bacterial, or cross-species miRNAs in infected samples. The application is widely used by biologists and bioinformaticians. 4. We have subsequently developed the web application Small RNA Expression Atlas (SEA). SEA is a fast, flexible, and fully interactive web application for the investigation of sRNA and pathogen expression across cell lines, tissues, diseases, organisms, and sRNA-species. Using SEA, we were able to detect pathogen signatures involved in dementia and detect potential novel biomarkers for Parkinson disease. Furthermore, it has been used for augmenting RNA-seq data in deep learning applications.
Publications
- Oasis: online analysis of small RNA deep sequencing data. BMC Bioinformatics 31 (13), 2205-2207 (2015)
Vincenzo Capece, Julio C Garcia Vizcaino, Ramon Vidal, Raza-Ur Rahman, Tonatiuh Pena Centeno, Orr Shomroni, Irantzu Suberviola, Andre Fischer, Stefan Bonn
(See online at https://doi.org/10.1093/bioinformatics/btv113) - DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nature neuroscience 19 (1), 102- (2016)
Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Garcia Vizcaino JC, Schuetz AL, Burkhardt S, Benito E, Navarro Sala M, Javan SB, Haass C, Schmid B, Fischer A, Bonn S
(See online at https://doi.org/10.1038/nn.4194) - Genome-wide chromatin and gene expression profiling during memory formation and maintenance in adult mice. Sci Data. 2016 Oct 11;3:160090. (2016)
Centeno TP, Shomroni O, Hennion M, Halder R, Vidal R, Rahman RU, Bonn S
(See online at https://doi.org/10.1038/sdata.2016.90) - Oasis 2: improved online analysis of small RNA-seq data. BMC Bioinformatics 19, Article number: 54 (2018)
Raza-Ur Rahman, Abhivyakti Gautam, Jörn Bethune, Abdul Sattar, Maksims Fiosins, Daniel Sumner Magruder, Vincenzo Capece, Orr Shomroni, Stefan Bonn
(See online at https://doi.org/10.1186/s12859-018-2047-z) - SEAweb: The small RNA Expression Atlas web application. Nucleic Acid Research (2019)
Raza-Ur Rahman, Vikas Bansal, Maksims Fiosins, Anna-Maria Liebhoff, Ashish Rajput, Abdul Sattar, Daniel Sumner Magruder, Sumit Madan, Ting Sun, Abhivyakti Gautam, Sven Heins, Timur Liwinski, Jörn Bethune, Claudia Trenkwalder, Juliane Fluck, Brit Mollenhauer, Stefan Bonn
(See online at https://doi.org/10.1093/nar/gkz869)
