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Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE189119 | GEO | 2023/01/09

REPOSITORIES: GEO

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Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome

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Project description:As part of our multimodal investigation fo FOXG1 functions at the chromatin, we report that there are both increase and decrease in chromatin accessibility upon reduced levels of FOXG1 in pirmary hippocampal neurons. The data presented in this study enlighten for the first time in a comprehensive manner diverse and multi-modal functions of FOXG1 at the chromatin level in mature neurons. Despite FOXG1 being recognized as a key transcription factor for telencephalic development and neuronal function, insights into the mechanism underlying transcriptional regulation are sparse. We here show that (i) FOXG1 acts both as repressor and activator, (ii) localizes predominantly to enhancer regions, (iii) alters the epigenetic landscape, (iv) affects directly HDAC functions, and (v) acts in concert with NEUROD1 to instruct transcriptional programs necessary for axono- and synaptogenesis.

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Project description:The forkhead box transcription factor FoxG1 is known to influence forebrain development by determining regional brain specification as well as by regulating expansion of neuronal progenitors and timing of their differentiation. In the adult brain, FoxG1 is expressed in cortex and hippocampus. In the latter it is involved in postnatal neurogenesis in the dentate gyrus by influencing maintenance of the progenitor pool as well as survival and maturation of postmitotic neurons. In humans, haploinsufficiency of FoxG1 causes the congenital version of the Rett syndrome, a progressive neurologic developmental disorder. We use FoxG1 mutant mice to screen for global changes in mRNA expression after partial loss of FoxG1 protein in hippocampi of six week-old mice. Data analysis points to a specific function for FoxG1 in adult hippocampus besides its known involvement in dentate gyrus neurogenesis. We analyse transcriptional changes in the different CA-fields and show that especially the CA-1 field is influenced by lack of FOXG1 protein. Furthermore, data analysis shows altered expression of genes that have also been implicated in the classical form of the Rett syndrome and other autism spectrum disorders.

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