AUTHOR=Sevilla Ana , Papatsenko Dimitri , Mazloom Amin R. , Xu Huilei , Vasileva Ana , Unwin Richard D. , LeRoy Gary , Chen Edward Y. , Garrett-Bakelman Francine E. , Lee Dung-Fang , Trinite Benjamin , Webb Ryan L. , Wang Zichen , Su Jie , Gingold Julian , Melnick Ari , Garcia Benjamin A. , Whetton Anthony D. , MacArthur Ben D. , Ma’ayan Avi , Lemischka Ihor R. TITLE=An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.630067 DOI=10.3389/fcell.2021.630067 ISSN=2296-634X 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.