We performed stochastic simulations of transcription factor (TF) molecules translocating by facilitated diffusion (a combination of 3D diffusion in the cytoplasm and 1D random walk on the DNA) , and consider various abundances of cognate and non-cognate TFs to assess the influence of competitor molecules thatalso move along the DNA . We show that molecular crowding on the DNA always leads to longer times required by TF molecules to locate their target sites as well as to lower occupancy, which may confer a general mechanism to control gene activity levels globally  . Finally, we show that crowding on the DNA may increase transcriptional noise through increased variability of the occupancy time of the target sites.
Transcription factor (TF) molecules translocate by facilitated diffusion (a combination of 3D diffusion around and 1D random walk on the DNA) . Despite the attention this mechanism received in the last 40 years, only a few studies investigated the influence of the cellular environment on the facilitated diffusion mechanism and, in particular, the influence of `other' DNA binding proteins competing with the TF molecules for DNA space. Molecular crowding on the DNA is likely to influence the association rate of TFs to their target site and the steady state occupancy of those sites, but it is still not clear how it influences the search in a genome-wide context, when the model includes biologically relevant parameters (such as: TF abundance, TF affinity for DNA and TF dynamics on the DNA). We performed stochastic simulations of TFs performing the facilitated diffusion mechanism, and considered various abundances of cognate and non-cognate TFs . We show that, for both obstacles that move on the DNA and obstacles that are fixed on the DNA, changes in search time are not statistically significant in case of biologically relevant crowding levels on the DNA. In the case of non-cognate proteins that slide on the DNA, molecular crowding on the DNA always leads to statistically significant lower levels of occupancy, which may confer a general mechanism to control gene activity levels globally . When the `other' molecules are immobile on the DNA, we found a completely different behaviour, namely: the occupancy of the target site is always increased by higher molecular crowding on the DNA . Finally, we show that crowding on the DNA may increase transcriptional noise through increased variability of the occupancy time of the target sites.
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We performed stochastic simulations of transcription
Transcription
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translocating
translocate
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in the cytoplasm
around
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, and consider
. Despite the attention this mechanism received in the last 40 years, only a few studies investigated the influence of the cellular environment on the facilitated diffusion mechanism and, in particular, the influence of `other' DNA binding proteins competing with the TF molecules for DNA space. Molecular crowding on the DNA is likely to influence the association rate of TFs to their target site and the steady state occupancy of those sites, but it is still not clear how it influences the search in a genome-wide context, when the model includes biologically relevant parameters (such as: TF abundance, TF affinity for DNA and TF dynamics on the DNA). We performed stochastic simulations of TFs performing the facilitated diffusion mechanism, and considered
R
to assess the influence of competitor molecules thatalso move along the DNA . We show that
. We show that, for both obstacles that move on the DNA and obstacles that are fixed on the DNA, changes in search time are not statistically significant in case of biologically relevant crowding levels on the DNA. In the case of non-cognate proteins that slide on the DNA,
R
longer times required by TF molecules to locate their target sites as well as to lower
statistically significant lower levels of
A
. When the `other' molecules are immobile on the DNA, we found a completely different behaviour, namely: the occupancy of the target site is always increased by higher molecular crowding on the DNA