To unravel the epigenetic regulation pathway of hippocampal neurogenesis in the adult mammalian brain, provide molecular insights of relevant human disease
Final Report Abstract
One of the most interesting questions in stem cell field is that how the stem cell-specific epigenetic landscape is established to guide a proper differentiation process. In the current project, we demonstrate that the chromatin remodeler CHD7, which is mutated in human CHARGE syndrome and cancers, is a master epigenetic regulator of neurogenesis and gliomagenesis. We first showed that CHD7 is specifically expressed in the neurogenic niches in the adult mouse brain. A neural stem cell specific mutation of CHD7 in adult mouse brain leads to dramatic reduction of neurogenesis in the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus. We also confirmed the neurogenesis defect phenotype by inactivating CHD7 during brain development. Strikingly, we found that physical exercise leads to a complete rescue of the CHD7 mutant phenotype in the hippocampus, suggesting for the first time a possible beneficial interference of the human CHARGE syndrome. We further found that CHD7 expression identifies a class of human brain tumors with a neuronal differentiation molecular signature. At last, we identified that two Sox group C genes, Sox4 and Sox11 are direct CHD7 target genes which are responsible for the neuronal differentiation defect in the CHD7 mutant. This study directly demonstrates the role of CHD7 in epigenetic regulation of neurogenesis, thus suggesting a general model of regulation of adult stem cells by chromatin regulators and providing strong implications for human diseases like the CHARGE syndrome and brain tumors. Most importantly, the role of CHD7 in human brain tumors provide a direct model to explain increasing mutations of chromatin regulators that are found from cancer genomic sequencing. It is very important to note that several recent studies identified that mutation of CHD8 leads to human Autism. It is known that CHD7 interact with CHD8 biochemically and CHARGE patients also have Autistic-like behavior, thus our study also provide significant insights into the molecular genetics of human Autism, which was poorly understand.
Publications
- (2013). The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors. Cell Stem Cell, 13, 62-72
Feng, W., Kahn, A., Bellvis P., Zhu, Z., Bernhardt, O., Herold-Mende, C., Liu, H.-K.
(See online at https://doi.org/10.1016/j.stem.2013.05.002)
