RT Journal Article
SR Electronic
T1 Branching and oscillations in the epigenetic landscape of cell-fate determination
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 007831
DO 10.1101/007831
A1 Jomar Fajardo Rabajantea
A1 Ariel Lagdameo Babierraa
YR 2014
UL http://biorxiv.org/content/early/2014/08/11/007831.abstract
AB Waddington’s epigenetic landscape is a famous sketch of cell-fate determination. This landscape is not static but varies because of the dynamic kinetics of gene regulation during development. Mathematical models of gene regulation usually contain fixed parameters and limited number of state variables, hence cannot fully characterize the landscape’s temporal transformation. Here we simulate a high-dimensional model of gene regulation with time-varying repression links among gene regulatory factors. We are able to show sequential multi-lineage differentiation at different timescales that portrays the branching canals in Waddington’s landscape. We also show that sustained oscillations by a repressilator-type network can activate suppressed genes while cells trail a flattened landscape. Gradient-based dynamics dampen the oscillations resulting in dedifferentiation to multipotency or pluripotency. Our theoretical results provide insights into the possible mechanisms of cell differentiation and associated diseases, such as cancer, as well as contribute in devising strategies for cellular reprogramming.