J. Comput. Biol. - Stochastic simulation of notch signaling reveals novel factors that mediate the differentiation of neural stem cells.

Tópicos

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Resumo

Notch signaling controls cell fate decisions and regulates multiple biological processes, such as cell proliferation, differentiation, and apoptosis. Computational modeling of the deterministic simulation of Notch signaling has provided important insight into the possible molecular mechanisms that underlie the switch from the undifferentiated stem cell to the differentiated cell. Here, we constructed a stochastic model of a Notch signaling model containing Hes1, Notch1, RBP-Jk, Mash1, Hes6, and Delta. mRNA and protein were represented as a discrete state, and 334 reactions were employed for each biochemical reaction using a graphics processing unit-accelerated Gillespie scheme. We employed the tuning of 40 molecular mechanisms and revealed several potential mediators capable of enabling the switch from cell stemness to differentiation. These effective mediators encompass different aspects of cellular regulations, including the nuclear transport of Hes1, the degradation of mRNA (Hes1 and Notch1) and protein (Notch1), the association between RBP-Jk and Notch intracellular domain (NICD), and the cleavage efficiency of the NICD. These mechanisms overlap with many modifiers that have only recently been discovered to modulate the Notch signaling output, including microRNA action, ubiquitin-mediated proteolysis, and the competitive binding of the RBP-Jk-DNA complex. Moreover, we identified the degradation of Hes1 mRNA and nuclear transport of Hes1 as the dominant mechanisms that were capable of abolishing the cell state transition induced by other molecular mechanisms.

Resumo Limpo

notch signal control cell fate decis regul multipl biolog process cell prolifer differenti apoptosi comput model determinist simul notch signal provid import insight possibl molecular mechan underli switch undifferenti stem cell differenti cell construct stochast model notch signal model contain hes notch rbpjk mash hes delta mrna protein repres discret state reaction employ biochem reaction use graphic process unitacceler gillespi scheme employ tune molecular mechan reveal sever potenti mediat capabl enabl switch cell stem differenti effect mediat encompass differ aspect cellular regul includ nuclear transport hes degrad mrna hes notch protein notch associ rbpjk notch intracellular domain nicd cleavag effici nicd mechan overlap mani modifi recent discov modul notch signal output includ microrna action ubiquitinmedi proteolysi competit bind rbpjkdna complex moreov identifi degrad hes mrna nuclear transport hes domin mechan capabl abolish cell state transit induc molecular mechan

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