Nono deficiency compromises TET1 chromatin association and impedes neuronal differentiation of mouse embryonic stem cells
| Autor: | Wenjing Li, Feizhen Wu, Li Tan, Yang Shi, Yujiang Geno Shi, Violetta Karwacki-Neisius, Chun Ma |
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| Rok vydání: | 2020 |
| Předmět: |
Transcription
Genetic AcademicSubjects/SCI00010 Neurogenesis Gene Knockout Techniques Mice 03 medical and health sciences Proto-Oncogene Proteins Genetics Animals RNA-Seq Epigenetics Cells Cultured 030304 developmental biology Regulation of gene expression 0303 health sciences biology Gene regulation Chromatin and Epigenetics 030302 biochemistry & molecular biology RNA-Binding Proteins Mouse Embryonic Stem Cells DNA-binding domain Embryonic stem cell Chromatin Cell biology DNA-Binding Proteins Gene Expression Regulation 5-Methylcytosine biology.protein Neuron differentiation Demethylase Stem cell |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | NONO is a DNA/RNA-binding protein, which plays a critical regulatory role during cell stage transitions of mouse embryonic stem cells (mESCs). However, its function in neuronal lineage commitment and the molecular mechanisms of its action in such processes are largely unknown. Here we report that NONO plays a key role during neuronal differentiation of mESCs. Nono deletion impedes neuronal lineage commitment largely due to a failure of up-regulation of specific genes critical for neuronal differentiation. Many of the NONO regulated genes are also DNA demethylase TET1 targeted genes. Importantly, re-introducing wild type NONO to the Nono KO cells, not only restores the normal expression of the majority of NONO/TET1 coregulated genes but also rescues the defective neuronal differentiation of Nono-deficient mESCs. Mechanistically, our data shows that NONO directly interacts with TET1 via its DNA binding domain and recruits TET1 to genomic loci to regulate 5-hydroxymethylcytosine levels. Nono deletion leads to a significant dissociation of TET1 from chromatin and dysregulation of DNA hydroxymethylation of neuronal genes. Taken together, our findings reveal a key role and an epigenetic mechanism of action of NONO in regulation of TET1-targeted neuronal genes, offering new functional and mechanistic understanding of NONO in stem cell functions, lineage commitment and specification. |
| Databáze: | OpenAIRE |
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