Gene Regulation
gene regulation
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Gene regulation networks in nervous system cancers: identification of novel drug targets
Activity-Dependent Gene Regulation in Health and Disease
In the last of this year’s Brain Prize webinars, Elizabeth Pollina (Washington University, USA), Eric Nestler (Icahn School of Medicine Mount Sinai, USA) and Michelle Monje (Stanford University, USA) will present their work on activity-dependent gene regulation in health and disease. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by the winners of the 2023 Brain Prize, Michael Greenberg, Erin Schuman and Christine Holt.
Shaping connections through remote gene regulation
In the third of this year’s Brain Prize webinars, Oscar Marin (King's College London, UK), Leslie Griffith (Brandeis University, USA), and Kesley Martin (Simons Foundation, USA) will present their work on shaping connections through remote gene regulation. Each speaker will present for 25 minutes, and the webinar will conclude with an open discussion. The webinar will be moderated by the winners of the 2023 Brain Prize, Michael Greenberg, Erin Schuman and Christine Holt.
Mechanisms of human cortical development and neuropsychiatric disease
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.
Modulating gene regulation to treat gene dosage-associated diseases
Fundamental Cellular and Molecular Mechanisms governing Brain Development
The symposium will start with Prof Cooper who will present “From neural tube to neocortex: the role of adhesion in maintaining stem cell morphology and function”. Then, Dr Tsai will talk about “In the search for new genes involved in brain development and disorders”. Dr Del Pino will deal with the “Regulation of intrinsic network activity during area patterning in the cerebral cortex”, and Dr Wang will present “Modelling Neurodevelopmental Disorders in Flies”.
Human neuronal activity-dependent gene regulation in development and disease
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