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SETDB1 Regulate Cell State Maintenance and Cell Fate Differentiation in DG

ABSTRACT: In this study, we explored the function of histone methyltransferase SETDB1 in the development of the mouse dentate gyrus (DG). We discovered that a critical role of Setdb1 in steering the early development path of DG NSCs towards adult neural stem cells and astrocytes destinies. In an effort to delineate the exact molecular mechanisms of aberrant postnatal NSCs and astrocytes caused by Setdb1-deleted NSCs, we utilized a suite of techniques including RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) and Setdb1-Flag Cleavage Under Targets and Tagmentation (CUT&Tag) in both wild-type (WT) and Setdb1-deficient DG samples. Combination of transcriptome and epigenome analysis indicate that COX6B2 as a key target of SETDB1 for regulating maintenance of early postnatal NSCs and differentiation of astrocytes. Taken together, our results highlight the importance of transcriptomic and chromatin landscapes for metabolic reprogramming and identify a exquisite mechanism underlyling the cell state maintenance and cell fate differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE293069 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:BACKGROUND: The polycomb group protein Ezh2 is an epigenetic repressor of transcription originally found to prevent untimely differentiation of pluripotent embryonic stem cells. We previously demonstrated that Ezh2 is also expressed in multipotent neural stem cells (NSCs). We showed that Ezh2 expression is downregulated during NSC differentiation into astrocytes or neurons. However, high levels of Ezh2 remained present in differentiating oligodendrocytes until myelinating. This study aimed to elucidate the target genes of Ezh2 in NSCs and in premyelinating oligodendrocytes (pOLs). METHODOLOGY/PRINCIPAL FINDINGS: We performed chromatin immunoprecipitation followed by high-throughput sequencing to detect the target genes of Ezh2 in NSCs and pOLs. We found 1532 target genes of Ezh2 in NSCs. During NSC differentiation, the occupancy of these genes by Ezh2 was alleviated. However, when the NSCs differentiated into oligodendrocytes, 393 of these genes remained targets of Ezh2. Analysis of the target genes indicated that the repressive activity of Ezh2 in NSCs concerns genes involved in stem cell maintenance, in cell cycle control and in preventing neural differentiation. Among the genes in pOLs that were still repressed by Ezh2 were most prominently those associated with neuronal and astrocytic committed cell lineages. Suppression of Ezh2 activity in NSCs caused loss of stem cell characteristics, blocked their proliferation and ultimately induced apoptosis. Suppression of Ezh2 activity in pOLs resulted in derangement of the oligodendrocytic phenotype, due to re-expression of neuronal and astrocytic genes, and ultimately in apoptosis. CONCLUSIONS/SIGNIFICANCE: Our data indicate that the epigenetic repressor Ezh2 in NSCs is crucial for proliferative activity and maintenance of neural stemness. During differentiation towards oligodendrocytes, Ezh2 repression continues particularly to suppress other neural fate choices. Ezh2 is completely downregulated during differentiation towards neurons and astrocytes allowing transcription of these differentiation programs. The specific fate choice towards astrocytes or neurons is apparently controlled by epigenetic regulators other than Ezh2. Examination of Ezh2 target sites in 2 different primary cells types

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SETDB1 Regulate Cell State Maintenance and Cell Fate Differentiation in DG

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