DNA Glycosylase-Dependent Regulation of the Neuronal Epigenome

In this project, we unraveled a novel function of DNA glycosylase-initiated repair in epigenetic remodeling in brain. Exogenous and endogenous oxidative agents continuously challenge genomic DNA, thus preserving genomic integrity is a key for development and health. Base excision repair (BER) is the major pathway for removal of oxidized bases in the genome. BER is initiated by DNA glycosylases, recognizing and excising a broad range of base lesions. However, the classical view of base lesions as fatal damage is recently challenged by several observations that indicate epigenetic-like function of these DNA modifications. Epigenetic mechanisms are critical to regulate transcription and are involved in brain functions such as cognitive processes. Increasing evidences indicate that BER is involved in modulating the epigenome but the impact of DNA glycosylases on the epigenetic landscape in brain remained largely unknown. Our results demonstrate that DNA glycosylases alter the epigenetic landscape of neuronal cells in an age-dependent manner. Increased oxidative stress, a phenomenon observed during aging is thereby facilitating an interaction of DNA glycosylases with an epigenetic modifier that suppresses transcriptional programs important for adult neuron function. A loss of this interaction leads to an open chromatin state and an aberrant activation of genes involved in cognitive processes. This might underly the memory impairment observed in DNA glycosylase-deficient mice.

This project has uncovered a novel layer of genome regulation that is important for brain function such as cognition. We have identified DNA glycosylases as regulator of the neuronal epigenome, a function that is not related to their known role in canonical BER. We show that they interact with epigenetic modifiers to remodel the epigenetic landscape under oxidative stress conditions and during aging. Thus, our project contributes to a new research direction with tremendous applications in diagnosis and treatment of age-related brain diseases.

In this project, I will use a multidisciplinary approach combining (epi)genomics, transcriptomics, proteomics, bioinformatics, molecular and cell biology and mouse genetics to elucidate the role of DNA glycosylases OGG1 and MUTYH-initiated base excision repair (BER) in regulation of the neuronal epigenome. BER is traditionally known to preserve genomic integrity by removing damaged bases. OGG1 and MUTYH cooperate to prevent mutations caused by the major oxidative DNA base lesion 8-oxoguanine (8-oxoG). However, increasing evidences suggest that BER is involved in modulating the epigenetic landscape and my recent work demonstrates a function of OGG1 and MUTYH in regulating gene expression related to anxiety and cognition. Moreover, my preliminary data indicate that OGG1 and MUTYH alter the hippocampal transcriptome in response to acute injury by remodeling the epigenetic landscape. I propose that accumulation of 8-oxoG at gene regulatory regions interferes with the neuronal epigenome to regulate distinct transcriptional networks important for brain function. To test this hypothesis, I will follow brain development in mice deficient for OGG1 and/or MUTYH and use single base resolution sequencing methods to identify the genomic context in which 8-oxoG and epigenetic modifications occur. Further, I will investigate whether alterations of the epigenome by OGG1 and MUTYH are important for memory formation. To reveal the mechanism how defective 8-oxoG repair interferes with epigenetic modifications and gene expression, OGG1 and/or MUTYH-deficient mouse and human cell lines will serve as model systems and reporter gene assays with specific promoter from target genes will be employed. Understanding the molecular mechanism of DNA glycosylases-dependent epigenetic remodeling in regulating the neuronal epigenome will lay the basis for novel therapeutic strategies for brain-related disorders.