Journal Article

An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program

Dai, David, Jensen, Holly A., Congleton, Johanna, Yen, Andrew, Sagar, Adithya, Varner, Jeffrey D., Rogers, Katharine V., Bunaciu, Rodica P., Tasseff, Ryan

2017

Overview

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 PPARg were critical to the ATRAinduced 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/31 / 13/51 / 13/95 / 631/114 / 631/553 / 82/1 / 96 / Cell Cycle Checkpoints / Cell Differentiation / Cell fate / Data processing / Epithelial-Mesenchymal Transition / Feedback / Gene expression / Gene Regulatory Networks - genetics / Granulocyte Precursor Cells - physiology / Guanine / Guanine nucleotide exchange factor / HL-60 Cells / Humanities and Social Sciences / Humans / Kinases / MAP kinase / Models, Theoretical / multidisciplinary / Oxidation-Reduction / Peroxisome proliferator-activated receptors / Phenotype / PPAR gamma - genetics / PPAR gamma - metabolism / Protein kinase / Proto-Oncogene Proteins c-vav - metabolism / Reactive Oxygen Species - metabolism / Retinoic acid / Science / Science (multidisciplinary) / Signal Transduction / Transcription factors / Tretinoin - metabolism