@article {Tasseff138784, author = {Ryan Tasseff and Holly A. Jensen and Johanna Congleton and Wei Dai and Katharine V. Rogers and Adithya Sagar and Rodica P. Bunaciu and Andrew Yen and Jeffrey D. Varner}, title = {An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program}, elocation-id = {138784}, year = {2017}, doi = {10.1101/138784}, publisher = {Cold Spring Harbor Laboratory}, abstract = {In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPAR$[gamma] were critical to the ATRA-induced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.}, URL = {https://www.biorxiv.org/content/early/2017/06/02/138784}, eprint = {https://www.biorxiv.org/content/early/2017/06/02/138784.full.pdf}, journal = {bioRxiv} }