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Phf23 regulates embryonic neurogenesis by increasing the level of H3K27ac of Tcf4 [RNA-seq]

ABSTRACT: Epigenetic regulation is an important cell fate modality that is ubiquitous in neural development and plays an important role in both the fate determination and differentiation of neural stem cells (NSCs). The epigenetic regulator Phf23 is widely expressed in different human tissues and is involved in various biological processes, but its functional role in development has rarely been reported. Here, we found that Phf23 is an important epigenetic regulator that maintains embryonic neurogenesis in mice, and its absence leads to inhibition of the acetylation level of H3K27ac through the function of Hdac2, resulting in the blockage of embryonic NSCs differentiation at embryonic day 13.5 (E13.5). Tcf4, a transcription factor closely associated with neurogenesis, is a key downstream target gene of Phf23 in regulating embryonic neurogenesis, which may provide insights into the neuromodulatory network of the brain and the diagnosis and treatment of clinically relevant diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE277737 | GEO | 2025/06/30

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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Phf23 regulates embryonic neurogenesis by increasing the level of H3K27ac of Tcf4 [RNA-seq]

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