Regulation of mRNA and role of ncRNAs in the molecular basis of cognitive features

• Applicants: Professor Dr. Andreas Kuss; Professor Dr. Stefan Simm
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458950132

Non-coding RNAs (ncRNAs) play key regulatory roles in shaping cellular activity and represent about 60% of total RNA in humans. The various ncRNAs are involved in the regulation of mRNA expression and epigenetic mechanisms. As such they were also found to play a role in the etiology of human disorders including not only cancer but also hereditary neurocognitive impairment. In this respect it was shown that specific pathways and functional interrelationships including different ncRNAs play a prominent role for intellectual disability. With the help of improved NGS techniques and applications it becomes possible to analyse the quality and quantity of ncRNA species, including circular RNAs (circRNAs) as well as long ncRNAs (lncRNAs), of which the functional characterization is still challenging. Therefore, we will establish an expression atlas of ncRNA and mRNA species in different murine tissues to see brain specific ncRNA-dependent effects in wild type and mutant mice. As a model we will use Ftsj1 deficient mice. FTSJ1 Deficiency in humans causes X-Chromosomal intellectual disability. The protein is involved in RNA-methylation and expressed in all tissues investigated to date, and it is still not known how this ubiquitously expressed gene leads to the comparatively restricted phenotype of non-syndromic intellectual disability.Besides getting a clearer picture as to the qualitative and quantitative amount of ncRNA in different tissues we will use the ncRNA datasets to train classification and prediction of ncRNA types using deep learning algorithms (e.g. convolutional neural nets; CNNs). Based on non-obvious patterns which can be trained and learned using unsupervised machine learning approaches, new putative ncRNAs as well as their genomic locations can be identified, and perhaps we will even be able to define putative subclasses for not so well defined ncRNA classes such as lncRNAs. To understand more about the molecular / cellular contexts and how they influence cognitive features, we want to compare ncRNAs in the brain and other tissues of a mouse model for intellectual disability. Here, the effects of regulation on mRNA (detected e.g. by "Ribosome Profiling" and "Degradome Sequencing") as well as modifications ("RiboMethSeq") and the expression of transcripts itself (RNA Sequencing) can complete the picture of regulation but need multi-omics approaches for their analysis. In our approach we combine the generation of basic data for broad and general use (e. g. mouse expression atlas) with an important increase in knowledge about the molecular processes involved in the development and maintenance of cognitive abilities.

• DFG Programme: Research Grants