  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.
