TY - JOUR

T1 - Pluripotency gene network dynamics

T2 - System views from parametric analysis

AU - Akberdin, Ilya R.

AU - Omelyanchuk, Nadezda A.

AU - Fadeev, Stanislav I.

AU - Leskova, Natalya E.

AU - Oschepkova, Evgeniya A.

AU - Kazantsev, Fedor V.

AU - Matushkin, Yury G.

AU - Afonnikov, Dmitry A.

AU - Kolchanov, Nikolay A.

PY - 2018/3/29

Y1 - 2018/3/29

N2 - Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed.

AB - Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed.

KW - Animals

KW - Gene Expression Regulation/physiology

KW - Gene Regulatory Networks/physiology

KW - Mice

KW - Models, Genetic

KW - Mouse Embryonic Stem Cells/cytology

KW - Transcription Factors/genetics

KW - EMBRYONIC STEM-CELL

KW - SELF-RENEWAL

KW - STATE

KW - HETEROGENEITY

KW - OCT4

KW - NANOG AUTOREPRESSION

KW - DIFFERENTIATION

KW - TRANSCRIPTIONAL REGULATION

KW - EXPRESSION

KW - FEEDBACK

UR - http://www.scopus.com/inward/record.url?scp=85044993707&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0194464

DO - 10.1371/journal.pone.0194464

M3 - Article

C2 - 29596533

AN - SCOPUS:85044993707

VL - 13

SP - e0194464

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 3

M1 - 0194464

ER -