Abstract
The nucleosome remodeling and deacetylation (NuRD) complex is required for modulating the transcription of essential pluripotency genes in ESC self-renewal. MBD3 is considered a key player in the formation of a functional NuRD complex. The recruitment of MBD3 to methylated promoters may require other prerequisite factors. We show that cyclin-dependent kinase 2-associated protein 1 (CDK2AP1), an essential gene for early embryonic development, plays a role in pluripotency of ESC by engaging MBD3 to the promoter region of Wnt signaling genes. The occupancy of MBD3 on several promoters of Wnt genes was significantly lost in the absence of CDK2AP1, resulting in hyperactivation of Wnt. We propose that the transcriptional modulation of the Wnt pathway mediated by NuRD requires the presence of essential auxiliary components such as CDK2AP1, which may aid the association of the complex with specific focal regions of the target promoters.
Highlights
Nucleosome remodeling is integral in transcriptional control, yet the exact mechanisms involved remain to be elucidated
We find that the molecular interaction between methyl-binding domain protein 3 (MBD3) and cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is essential for the epigenetic regulation of the Wnt signaling pathway in mESCs
Deletion of Cdk2ap1 Leads to Global Methylomic and Transcriptomic Changes—To date, the role of nucleosome remodeling and deacetylation (NuRD) in transcriptional regulation, signaling, and chromatin remodeling in the context of self-renewal is not fully understood (35)
Summary
Nucleosome remodeling is integral in transcriptional control, yet the exact mechanisms involved remain to be elucidated. The nucleosome remodeling and deacetylation (NuRD) complex is required for modulating the transcription of essential pluripotency genes in ESC self-renewal. We show that cyclin-dependent kinase 2-associated protein 1 (CDK2AP1), an essential gene for early embryonic development, plays a role in pluripotency of ESC by engaging MBD3 to the promoter region of Wnt signaling genes. The occupancy of MBD3 on several promoters of Wnt genes was significantly lost in the absence of CDK2AP1, resulting in hyperactivation of Wnt. We propose that the transcriptional modulation of the Wnt pathway mediated by NuRD requires the presence of essential auxiliary components such as CDK2AP1, which may aid the association of the complex with specific focal regions of the target promoters. We propose a model that shows there are essential auxiliary components, such as CDK2AP1, that aid the association of the NuRD complex to specific promoters and mediate epigenetic regulation of regions of importance in controlling genes responsible for stem cell pluripotency
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