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Epigenetics in the development and function of the cortical GABAergic system

Deficits in the function of inhibitory GABAergic interneurons of the cerebral cortex are implicated in the pathophysiology of schizophrenia, major depressive disorder, bipolar disorder, Alzheimer’s disease and Parkinson’s disease. Such disorders in part rely on defective development; for these, the migration from sites of origin to the cortical targets represents a critical step. To investigate this we use different stage-specific conditional KO mouse models to approach the function and mode of action of the DNA methyltransferase 1 during interneuron development with focus on migration, as well as in sustaining adult interneuron functionality. We investigate the DNMT1-dependent regulation of discrete subcellular processes like endocytosis, thereby acting on neurons’ physiology and cellular memory. We are further interested in how environmental stimuli affect the epigenomic DNMT1-dependent configurations.

Epigenetic key players in neurodegeneration

The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated and neurodegenerative diseases. Subordinate to genetic networks, epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal functionality and aging, and emerge to contribute to pathophysiology of neurodegenerative diseases. DNA methylation, which is a dynamic and reversible process being implicated in synaptic function and memory formation, is executed by DNA methyltransferases (DNMTs). In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by a crosstalk with histone modifications, thereby increasing the complexity of epigenetic transcriptional networks. DNMT1 was previously shown to promote the survival and function in the developing and adult brain by canonic and non-canonical actions. While being critical for neuronal development and function, DNMT1 negatively influences neuronal survival in aged brains. We have evidence that for a DNMT1-dependent regulation of the proteostasis network, which is prerequisite for neuronal function, long-term survival and in neurodegenerative contexts. For this, we currently investigate whether DNMT1 affects critical aspects of the proteostasis network.

The role of lncRNAs in targeting DNA methylation

Epigenetic signatures, such as DNA methylation, are known to be responsive to external stimuli, thus providing a mechanism for how environmental information is integrated into our genome. We want to improve the understanding of how writers of DNA methylation are directed to discrete genome sites upon stimulation with particular cues, that elicit known physiological responses in neurons. We focus on the role of long non-coding RNA (lncRNA) in directing DNA methylation. LncRNAs with critical functions in neuronal development are known to interact with DNMTs, that catalyze DNA methylation. Two models of lncRNA-mediated control of DNA methylation targeting have been proposed: 1) a prevention and 2) promotion of site-specific or non-site-specific DNA methylation by lncRNA-mediated sequestration of DNMTs to specific gene loci. We aim to decipher lncRNA species and structure motifs, that impede or facilitate locus-specific and non-site-specific DNA methylation in neuronal cells. Moreover, it will be assessed whether and how the lncRNA-mediated targeting of DNMT1 can be modulated by external stimuli. To this end, we apply innovative methods, such as ChIP and CLIP, in combination with Next Generation Sequencing and the Nanopore technology.

Epigenetic regulation of interneurons involved in multisensory processing

Classically, sensory modalities were studied in isolation. However, in natural settings, characterized by diverse sensory stimuli, perception is a multisensory process, integrating different modalities into a unified percept. The classic example is the relevance of lip movements as visual cues for improved speech perception in noisy environments. As multimodal integration is considered as a context-dependent, flexible and adaptive process, distinct mechanisms likely contribute to multimodal integration. Epigenetic mechanisms were shown to be involved in interneuron function and could potentially explain the dynamic properties of multisensory processing. Although inhibitory GABAergic interneurons, in particular parvalbumin (PV)-positive cortical interneurons, emerge as key players of multimodal visual-tactile and auditory-visual integration circuits by suppressing the non-dominant stimuli, the functional implication of epigenetic regulation in multimodal processing is unknown. Moreover, it remains elusive whether multimodal interneurons are characterized by different genetic and epigenetic traits distinguishing their function from unimodal operating interneurons. That is why we address these questions within the scope of our participation in the graduate college RTG2416 MultiSenses – MultiScales.

The epigenetic mechanisms underlying glioma pathogenesis

Gliomas are highly complex and heterogeneous brain tumors that have a poor prognosis, presenting significant challenges for clinicians and researchers. Recent studies have highlighted the close relationship between glioma development and various epigenetic phenomena, including chromatin remodeling, histone modifications, DNA methylation, and non-coding RNAs. The reversible nature of these epigenetic modifications has led to the identification of novel targets in glioma treatment, focusing on the proteins and genes that control these changes.

Our research aims to unravel how environmental signals can leave lasting marks on our genome and influence gene expression. We investigate the role of epigenetic mechanisms as a bridge between environmental cues and transcriptional regulation, seeking to understand their contribution to the transformation of normal cells into cancerous ones. Additionally, we aim to lay the groundwork for new targeted therapies.

In this context, our group specifically focuses on the ephrinA5-mediated activation of Eph receptors and understanding its impact on transcriptional changes underlying cellular responses in glioblastoma cells, such as migration. We explore how ephrinA5-induced Eph receptor signaling modulates the expression and function of long non-coding RNAs (lncRNAs) in glioma cells, and its impact on the recruitment of epigenetic writers like DNMTs, which exert transcriptional control via DNA methylation, ultimately leading to transcriptional changes. By dissecting this mechanism, we aim to uncover a potential new pathway through which ephrinA5 mediates tumor suppressive functions in glioblastoma multiforme (GBM). This discovery could provide a foundation for identifying novel therapeutic targets for GBM treatment.