A new mechanism of stem cell differentiation through slow binding/unbinding of regulators to genes

Abstract

Understanding differentiation, a biological process from a multipotent stem or progenitor state to a mature cell is critically important. We developed a theoretical framework to quantify the underlying potential landscape and pathways for cell development and differentiation. We proposed a new mechanism of differentiation and found the differentiated states can emerge from the slow binding/unbinding of regulatory proteins to gene promoters. With slow promoter binding/unbinding, we found multiple meta-stable differentiated states, which can explain the origin of multiple states observed in recent experiments. The kinetic time for the differentiation and reprogramming strongly depends on the time scale of the promoter binding/unbinding processes. We discovered an optimal speed for differentiation for certain promoter binding/unbinding rates. Future experiments might be able to tell if cells differentiate at that optimal speed. We also quantified irreversible kinetic pathways for the differentiation and reprogramming, which captures the non-equilibrium dynamics in multipotent stem or progenitor cells.

Stem cell differentiation as a many-body problem

“…S3, leads to consistent conclusions. We note transition through an intermediate state with low Nanog expression along the differentiation pathway has also been observed in previous studies (8,(14)(15)(16)39).…”

“…2A are obtained from calculations performed in the adiabatic limit, and the DNA occupancy states are assumed to achieve a conditional equilibrium. This assumption is, however, not always valid for eukaryotic cells because of slow chromatin dynamics (12,(14)(15)(16). To investigate the effect of DNA-binding kinetics on the epigenetic landscape, we determined the number of steady-state solutions for the stem cell network over a wide range of DNA-unbinding rates.…”

“…The high-level architecture of chromatin can severely limit the access of transcription factors to the DNA, slowing down DNA-binding kinetics (11,12) and resulting in gene expression noise deviating from Poisson statistics (13). Even when the transcription factors function as pioneers that can directly bind with the chromatin sites occupied by the nucleosome, slow DNA binding (14,15) is still a good approximation to describe the effect of the progressive change of the chromatin structure and histone modification induced by the pioneer factors on gene regulation (16). As a result, DNA binding must be treated on equal footing together with protein synthesis and degradation to fully understand eukaryotic gene regulation (14)(15)(16)(17)(18).…”

Quantifying Waddington landscapes and paths of non-adiabatic cell fate decisions for differentiation, reprogramming and transdifferentiation

“…As a result of the statistical analysis, we obtained the steady-state probability distribution, and further the potential landscape, according to U ¼ 2lnP ss [13,21,23,[25][26][27][34][35][36][37][38][39][40]. Here, P ss is the steady-state probability distribution in the state space of relative gene expression levels.…”

“…However, in eukaryotic cells, the effective binding/unbinding process can be comparable or even slower than the corresponding synthesis and degradation of proteins (non-adiabatic limit) owing to, for example, the slow entry of regulators to the cell nucleus, transcription initiation or epigenetics of DNA methylation and histone modification. Non-adiabatic effects can introduce new timescales and induce important changes, such the appearance of non-trivial stable states and generating additional fluctuations other than those generated by intrinsic and extrinsic sources [13][14][15][16][17][18][19][20][21][22][23].…”