PT  - JOURNAL ARTICLE
AU  - Ryan Tasseff
AU  - Holly A. Jensen
AU  - Johanna Congleton
AU  - Wei Dai
AU  - Katharine V. Rogers
AU  - Adithya Sagar
AU  - Rodica P. Bunaciu
AU  - Andrew Yen
AU  - Jeffrey D. Varner
TI  - An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program
AID  - 10.1101/138784
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 138784
4099  - http://biorxiv.org/content/early/2017/06/02/138784.short
4100  - http://biorxiv.org/content/early/2017/06/02/138784.full
AB  - 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.