An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feedback Interactions [gene expression]

Cell fate decisions during development are governed by multi-factorial regulatory mechanisms including chromatin remodelling, 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. Analyses of coordinated expression changes identified strikingly different epigenetic regulatory patterns of pluripotency and differentiation states. 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 Total of 12 samples; Esrrb day0, Esrrb kd day1, Esrrb kd day3 and Esrrb kd Day5; all performed in triplicates. Affymetrix GeneChip® Mouse Gene 1.0 ST arrays analyses of mouse embryonic stem cell gene expression profiles in the presence of day0 or upon knockdown of Esrrb at different time points day1, day3 and day5