“ATF6 Promotes Early Stem Cell Development”

Stem cells have scant and simplified organelles. The endoplasmic reticulum (ER) is the organelle of protein assembly, protein folding and protein maturation. The Unfolded Protein Response (UPR) is the regulatory mechanism that supports ER function and homeostasis. We identified significant expansion of the ER and the UPR regulators, IRE1, PERK, and ATF6, during early human embryonic stem cell development. Interestingly, the ATF6 pathway, but not the IRE1 or PERK pathways, was found to be strongly activated during early differentiation. Over‐expression of the transcriptional activator bZIP domain of ATF6 led to a dramatic increase of ER in hESCs. By contrast, pharmacologic inhibition of ATF6 cleavage by S1P reduced ER growth. We obtained similar findings using induced pluripotent stem cells (iPSCs), generated from achromatopsia patients that carry the loss‐of‐function R342C mutation in ATF6. In mutant ATF6 iPS cells, growth of the ER was significantly impaired during early stem cell differentiation when compared to wild‐type ATF6 iPS cells. Last, we found that ATF6 expression enhanced the acquisition of germ layer (ectoderm, mesoderm, endoderm) markers while ATF6 inhibition impaired acquisition of differentiation markers. We further identified that ATF6 expression can be stimulated by the FGF2 signaling cascade during these early differentiation steps. In summary, we identify a novel function for ATF6 in stem cells to promote ER expansion coupled with differentiation. Our findings suggest defects in stem cell differentiation may contribute to the early pathologies seen in human patients bearing loss‐of‐function ATF6 mutations.