Abstract
Cell fate decisions during development are governed by multi-factorial regulatory mechanisms including chromatin remodeling, DNA methylation, binding of transcription factors to specific loci, RNA transcription and protein synthesis. However, the mechanisms by which such regulatory “dimensions” coordinate cell fate decisions are currently poorly understood. Here we quantified the multi-dimensional molecular changes that occur in mouse embryonic stem cells (mESCs) upon depletion of Estrogen related receptor beta (Esrrb), a key pluripotency regulator. Comparative analyses of expression changes subsequent to depletion of Esrrb or Nanog, indicated that a system of interlocked feed-forward loops involving both factors, plays a central part in regulating the timing of mESC fate decisions. Taken together, our meta-analyses support a hierarchical model in which pluripotency is maintained by an Oct4-Sox2 regulatory module, while the timing of differentiation is regulated by a Nanog-Esrrb module.
Highlights
Understanding how embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively) regulate cell fate decisions is crucial to realizing their biomedical potential (Liu et al, 2020)
Along with the structural analysis of the pluripotency gene regulatory network architecture (PGRN), we have found a hierarchical model in which pluripotency is maintained by an Oct4-Sox2 regulatory module, while the timing of differentiation is regulated by a Nanog-Estrogen related receptor beta (Esrrb)
In order to explore the function of Esrrb and the Nanog/Esrrb module we analyzed genome wide epigenetic, transcriptional and post-transcriptional processes regulated by Esrrb
Summary
Understanding how embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively) regulate cell fate decisions is crucial to realizing their biomedical potential (Liu et al, 2020). The diverse phenotypic outputs of the core transcriptional puripotency and self-renewal network are directly or indirectly determined by genetic programs regulated via TF binding to the promoter regions of pluripotency regulators and differentiation inducers and this is mediated through changes in epigenetic states of DNA and chromatin at specific loci. From this point of view, network regulatory functions have clear multidimensionality. The goal of the current study is to elucidate global dynamic changes across multiple regulatory dimensions promoted by the depletion of Estrogen related receptor beta (Esrrb), a major core pluripotency TF
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