Methyl-CpG-Binding Protein MBD1 Regulates Neuronal Lineage Commitment through Maintaining Adult Neural Stem Cell Identity.

Methyl-CpG-binding domain 1 (MBD1) belongs to a family of methyl-CpG-binding proteins that are epigenetic "readers" linking DNA methylation to transcriptional regulation. MBD1 is expressed in neural stem cells residing in the dentate gyrus of the adult hippocampus (aNSCs) and MBD1 deficiency leads to reduced neuronal differentiation, impaired neurogenesis, learning deficits, and autism-like behaviors in mice; however, the precise function of MBD1 in aNSCs remains unexplored. Here, we show that MBD1 is important for maintaining the integrity and stemness of NSCs, which is critical for their ability to generate neurons. MBD1 deficiency leads to the accumulation of undifferentiated NSCs and impaired transition into the neuronal lineage. Transcriptome analysis of neural stem and progenitor cells isolated directly from the dentate gyrus of MBD1 mutant (KO) and WT mice showed that gene sets related to cell differentiation, particularly astrocyte lineage genes, were upregulated in KO cells. We further demonstrated that, in NSCs, MBD1 binds and represses directly specific genes associated with differentiation. Our results suggest that MBD1 maintains the multipotency of NSCs by restraining the onset of differentiation genes and that untimely expression of these genes in MBD1-deficient stem cells may interfere with normal cell lineage commitment and cause the accumulation of undifferentiated cells. Our data reveal a novel role for MBD1 in stem cell maintenance and provide insight into how epigenetic regulation contributes to adult neurogenesis and the potential impact of its dysregulation. SIGNIFICANCE STATEMENT: Adult neural stem cells (aNSCs) in the hippocampus self-renew and generate neurons throughout life. We show that methyl-CpG-binding domain 1 (MBD1), a DNA methylation "reader," is important for maintaining the integrity of NSCs, which is critical for their neurogenic potency. Our data reveal a novel role for MBD1 in stem cell maintenance and provide insight into how epigenetic regulation preserves the multipotency of stem cells for subsequent differentiation.