Histone
histone modification
At the nexus of genes, aging and environment: Understanding transcriptomic and epigenomic regulation in Parkinson's disease
Parkinson’s Disease (PD), the most common neurodegenerative movement disorder, is based on a complex interplay between genetic predispositions, aging processes, and environmental influences. In order to better understand the gene-environment axis in PD, we pursue a multi-omics approach to comprehensively interrogate genome-wide changes in histone modifications, DNA methylation, and hydroxymethylation, accompanied by transcriptomic profiling in cell and animal models of PD as well as large patient cohorts. Furthermore, we assess the plasticity of epigenomic modifications under influence of environmental factors using longitudinal cohorts of sporadic PD cases as well as mouse models exposed to specific environmental factors. Here, we present gene expression changes in PD mouse models in context of aging as well as environmental enrichment and high-fat diet.
Epigenetic regulation of alternative splicing in the context of cocaine reward
Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.
Integration of „environmental“ information in the neuronal epigenome
The inhibitory actions of the heterogeneous collection of GABAergic interneurons tremendously influence cortical information processing, which is reflected by diseases like autism, epilepsy and schizophrenia that involve defects in cortical inhibition. Apart from the regulation of physiological processes like synaptic transmission, proper interneuron function also relies on their correct development. Hence, decrypting regulatory networks that direct proper cortical interneuron development as well as adult functionality is of great interest, as this helps to identify critical events implicated in the etiology of the aforementioned diseases. Thereby, extrinsic factors modulate these processes and act on cell- and stage-specific transcriptional programs. Herein, epigenetic mechanisms of gene regulation, like DNA methylation executed by DNA methyltransferases (DNMTs), histone modifications and non-coding RNAs, call increasing attention in integrating “environmental information” in our genome and sculpting physiological processes in the brain relevant for human mental health. Several studies associate altered expression levels and function of the DNA methyltransferase 1 (DNMT1) in subsets of embryonic and adult cortical interneurons in patients diagnosed with schizophrenia. Although accumulating evidence supports the relevance of epigenetic signatures for instructing cell type-specific development, only very little is known about their functional implications in discrete developmental processes and in subtype-specific maturation of cortical interneurons. Similarly, little is known about the role of DNMT1 in regulating adult interneurons functionality. This talk will provide an overview about newly identified and roles DNMT1 has in orchestrating cortical interneuron development and adult function. Further, this talk will report about the implications of lncRNAs in mediating site-specific DNA methylation in response to discrete external stimuli.