Defining an essential transcription factor program for naive pluripotency

S.-J. Dunn1,*, G. Martello2,*,†‡, B. Yordanov1,*, S. Emmott1, A. G. Smith2,3,†
1Computational Science Laboratory, Microsoft Research, Cambridge CB1 2FB, UK.
2Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
3Department of Biochemistry, University of Cambridge, Cambridge, UK.
Department of Molecular Medicine, University of Padua, 35131 Padua, Italy.
†Corresponding author. E-mail: graziano.martello@unipd.it (G.M.); austin.smith@cscr.cam.ac.uk (A.G.S.)
* These authors contributed equally to this work.

Abstract

The gene regulatory circuitry through which pluripotent embryonic stem (ES) cells choose between self-renewal and differentiation appears vast and has yet to be distilled into an executive molecular program. We developed a data-constrained, computational approach to reduce complexity and to derive a set of functionally validated components and interaction combinations sufficient to explain observed ES cell behavior. This minimal set, the simplest version of which comprises only 16 interactions, 12 components, and three inputs, satisfies all prior specifications for self-renewal and furthermore predicts unknown and nonintuitive responses to compound genetic perturbations with an overall accuracy of 70%. We propose that propagation of ES cell identity is not determined by a vast interactome but rather can be explained by a relatively simple process of molecular computation.