Biology subjects

Abentung, A.

Publications and source records attributed to Abentung, A..

3 recordsLinked to original sources

bioRxiv2024

DNA glycosylases Ogg1 and Mutyh mediate gene expression of PRC2 target genes important for neuronal processes underlying memory formation

Base excision repair (BER) initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Recently, several DNA glycosylases were identified as potential readers of epigenetic modifications and proteins involved in BER have been associated with active DNA demethylation. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognitive function and independent of global DNA damage accumulation. However, the mechanism of DNA glycosylases in regulating cognition and their role in epigenetic remodeling in the brain remains elusive. Here we report that the combined deficiency of Ogg1 and Mutyh impairs spatial but not associative long-term memory. We demonstrate that Ogg1 or Mutyh modulate DNA methylation at gene regulatory regions of polycomb repressive complex 2 (PRC2) target genes in the adult hippocampus. Moreover, we find that the distribution of the PRC2 complex and histone modifications associated with PRC2 activity changes in both hippocampal neurons and glia depend on Ogg1 and Mutyh. Epigenetic alterations correlated with cell-type specific gene expression changes which were associated with pathways important for neuronal function and cognition. Our results provide a novel role for Ogg1 and Mutyh beyond DNA repair in modulating the epigenome to control transcriptional responses in the brain important for memory formation.

neuroscience↗

bioRxiv2024

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

8-oxo-7,8-dihydroguanine (OG) is one of the most abundant oxidative lesions in the genome and associated with genome instability. Its mutagenic potential is counteracted by a concerted action of 8-oxoguanine DNA glycosylase (OGG1) and mutY homolog DNA glycosylase (MUTYH). It has been suggested that OG and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA-sequencing to correlate genome-wide distribution of OG with gene transcription in OGG1 and/or MUTYH-deficient cells. Our data identified moderate enrichment of OG in the genome that is mainly dependent on the genomic context and not affected by DNA glycosylase-initiated repair. Interestingly, no association was found between genomic OG deposition and gene expression changes upon loss of OGG1 and MUTYH. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that OG functions as a cellular stress sensor to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.

genomics↗

bioRxiv2020

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

Neurons and oligodendrocytes are terminally differentiated cells that sustain cascades of gene activation and repression to execute highly specialized functions, while retaining homeostatic control. To study long-range chromatin folding without disturbing the native tissue environment, we developed Genome Architecture Mapping in combination with immunoselection (immunoGAM), and applied it to three cell types from the adult murine brain: dopaminergic neurons (DNs) from the midbrain, pyramidal glutamatergic neurons (PGNs) from the hippocampus, and oligodendroglia (OLGs) from the cortex. We find cell-type specific 3D chromatin structures that relate with patterns of gene expression at multiple genomic scales, including extensive reorganization of topological domains (TADs) and chromatin compartments. We discover the loss of TAD insulation, or TAD melting, at long genes (>400 kb) when they are highly transcribed. We find many neuron-specific contacts which contain accessible chromatin regions enriched for putative binding sites for multiple neuronal transcription factors, and which connect cell-type specific genes that are associated with neurodegenerative disorders such as Parkinsons disease, or specialized functions such as synaptic plasticity and memory. Lastly, sensory receptor genes exhibit increased membership in heterochromatic compartments that establish strong contacts in brain cells. However, their silencing is compromised in a subpopulation of PGNs with molecular signatures of long-term potentiation. Overall, our work shows that the 3D organization of the genome is highly cell-type specific, and essential to better understand mechanisms of gene regulation in highly specialized tissues such as the brain.

molecular biology↗