RT Journal Article
SR Electronic
T1 An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 138784
DO 10.1101/138784
A1 Ryan Tasseff
A1 Holly A. Jensen
A1 Johanna Congleton
A1 Wei Dai
A1 Katharine V. Rogers
A1 Adithya Sagar
A1 Rodica P. Bunaciu
A1 Andrew Yen
A1 Jeffrey D. Varner
YR 2017
UL http://biorxiv.org/content/early/2017/06/02/138784.abstract
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.