Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome
| Autor: | Ipek Akol, Annalisa Izzo, Fabian Gather, Stefanie Strack, Stefanie Heidrich, Darren Ó hAilín, Alejandro Villarreal, Christine Hacker, Tudor Rauleac, Chiara Bella, Andre Fischer, Thomas Manke, Tanja Vogel |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Neurod1 protein
mouse metabolism [Chromatin] metabolism [Hippocampus] genetics [Basic Helix-Loop-Helix Transcription Factors] axonogenesis Nerve Tissue Proteins Epigenesis Genetic Mice Basic Helix-Loop-Helix Transcription Factors Animals histone modification neuronal differentiation genetics [Nerve Tissue Proteins] Multidisciplinary metabolism [Nerve Tissue Proteins] Rett-syndrome metabolism [Forkhead Transcription Factors] Forkhead Transcription Factors ATAC Chromatin metabolism [Basic Helix-Loop-Helix Transcription Factors] genetics [Chromatin] genetics [Forkhead Transcription Factors] genetics [Rett Syndrome] Foxg1 protein mouse ddc:500 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 120(2), e2122467120 (2023). doi:10.1073/pnas.2122467120 Proceedings of the National Academy of Sciences of the United States of America |
| DOI: | 10.1073/pnas.2122467120 |
| Popis: | Forkhead box G1 (FOXG1) has important functions in neuronal differentiation and balances excitatory/inhibitory network activity. Thus far, molecular processes underlying FOXG1 function are largely unexplored. Here, we present a multiomics data set exploring how FOXG1 impacts neuronal maturation at the chromatin level in the mouse hippocampus. At a genome-wide level, FOXG1 i) both represses and activates transcription, ii) binds mainly to enhancer regions, iii) reconfigures the epigenetic landscape through bidirectional alteration of H3K27ac, H3K4me3, and chromatin accessibility, and iv) operates synergistically with NEUROD1. Interestingly, we could not detect a clear hierarchy of FOXG1 and NEUROD1, but instead, provide the evidence that they act in a highly cooperative manner to control neuronal maturation. Genes affected by the chromatin alterations impact synaptogenesis and axonogenesis. Inhibition of histone deacetylases partially rescues transcriptional alterations upon FOXG1 reduction. This integrated multiomics view of changes upon FOXG1 reduction reveals an unprecedented multimodality of FOXG1 functions converging on neuronal maturation. It fuels therapeutic options based on epigenetic drugs to alleviate, at least in part, neuronal dysfunction. |
| Databáze: | OpenAIRE |
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