The temporal dynamics of the concentrations of several proteins are tightly regulated, particularly for critical nodes in biological networks such as transcription factors. An important mechanism to control transcription factor levels is through autoregulatory feedback loops where the protein can bind its own promoter. Here we use theoretical tools and computational simulations to further our understanding of transcription-factor autoregulatory loops. We show that the stochastic dynamics of feedback and mRNA synthesis can significantly influence the speed of response of autoregulatory genetic networks toward external stimuli. The fluctuations in the response-times associated with the accumulation of the transcription factor in the presence of negative or positive autoregulation can be minimized by confining the ratio of mRNA/protein lifetimes within 1:10. This predicted range of mRNA/protein lifetime agrees with ranges observed empirically in prokaryotes and eukaryotes. The theory can quantitatively and systematically account for the influence of regulatory element binding and unbinding dynamics on the transcription-factor concentration rise-times. The simulation results are robust against changes in several system parameters of the gene expression machinery. © 2011 Biophysical Society.

Rajamanickam Murugan

Department Of Biotechnology

messenger RNA

transcription factor

article

biological model

Biosynthesis

gene expression regulation

gene regulatory network

genetics

Kinetics

metabolism

Statistics

Gene Regulatory Networks

Models, Biological

RNA, Messenger

Stochastic Processes

Transcription Factors

Eukaryota

Prokaryota

Fulltext

IIT Madras is a public technical and research university located in Chennai, Tamil Nadu. Founded in 1959, it is recognised as an Institute of National Importance.

IIT Madras has been ranked as the top engineering institute in India for four years in a row by the National Institutional Ranking Framework of the MHRD

It currently offers undergraduate, postgraduate and research degrees across 16 disciplines in Engineering, Sciences, Humanities and Management. About 596 faculty belonging to science and engineering departments and centres of the Institute are engaged in teaching, research and industrial consultancy.

IIT Madras

Biophysical Journal

We develop a detailed theoretical framework for various types of transcription factor gene oscillators. We further demonstrate that one can build genetic-oscillators which are tunable and robust against perturbations in the critical control parameters by coupling two or more independent Goodwin-Griffith oscillators through either -OR- or -AND- type logic. Most of the coupled oscillators constructed in the literature so far seem to be of -OR- type. When there are transient perturbations in one of the -OR- type coupled-oscillators, then the overall period of the system remains constant (period-buffering) whereas in case of -AND- type coupling the overall period of the system moves towards the perturbed oscillator. Though there is a period-buffering, the amplitudes of oscillators coupled through -OR- type logic are more sensitive to perturbations in the parameters associated with the promoter state dynamics than -AND- type. Further analysis shows that the period of -AND- type coupled dual-feedback oscillators can be tuned without conceding on the amplitudes. Using these results we derive the basic design principles governing the robust and tunable synthetic gene oscillators without compromising on their amplitudes. © 2014 Rajamanickam Murugan.

PLoS ONE

Theory on the dynamics of oscillatory loops in the transcription factor networks

Feedforward loops (FFLs) consist of three genes which code for three different transcription factors A, B and C where B regulates C and A regulates both B and C. We develop a detailed model to describe the dynamical behavior of various types of coherent and incoherent FFLs in the transcription factor networks. We consider the deterministic and stochastic dynamics of both promoter-states and synthesis and degradation of mRNAs of various genes associated with FFL motifs. Detailed analysis shows that the response times of FFLs strongly dependent on the ratios (wh = γpc/γph where h = a, b, c corresponding to genes A, B and C) between the lifetimes of mRNAs (1/γmh) of genes A, B and C and the protein of C (1/γpc). Under strong binding conditions we can categorize all the possible types of FFLs into groups I, II and III based on the dependence of the response times of FFLs on wh. Group I that includes C1 and I1 type FFLs seem to be less sensitive to the changes in wh. The coherent C1 type seems to be more robust against changes in other system parameters. We argue that this could be one of the reasons for the abundant nature of C1 type coherent FFLs. © 2012 Rajamanickam Murugan.

Theory on the dynamics of feedforward loops in the transcription factor networks

We develop a theory that explains how the thermally driven conformational fluctuations in the DNA binding domains (DBDs) of the DNA binding proteins (DBPs) are effectively coupled to the one-dimensional searching dynamics of DBPs for their cognate sites on DNA. We show that the rate γopt, associated with the flipping of conformational states of DBDs beyond which the maximum search efficiency of DBPs is achieved, varies with the one-dimensional sliding length L as γopt ∝ L-2 and with the number of roadblock protein molecules present on the same DNA m as γopt ∝ m2. The required free energy barrier ERTO associated with this flipping transition seems to be varying with L as ERTO ∝ In L2. When the barrier height associated with the conformational flipping of DBDs is comparable with that of the thermal free energy, then the possible value of L under in vivo conditions seems to be L ≤ 70 bps. © 2010 by the Biophysical Society.

Theory of site-Specific DNA-Protein interactions in the presence of conformational fluctuations of DNA binding domains

In this paper, we develop a theory on the mechanism of distal action of the transcription factors, which are bound at their respective cis-regulatory enhancer modules on the promoter-RNA polymerase II (PR) complexes to initiate the transcription event in eukaryotes. We consider both the looping and tracking modes of their distal communication and calculate the mean first passage time that is required for the distal interactions of the complex of enhancer and transcription factor with the PR via both these modes. We further investigate how this mean first passage time is dependent on the length of the DNA segment (L, base-pairs) that connects the cis-regulatory binding site and the respective promoter. When the radius of curvature of this connecting segment of DNA is R that was induced upon binding of the transcription factor at the cis-acting element and RNAPII at the promoter in cis-positions, our calculations indicate that the looping mode of distal action will dominate when L is such that L &gt; 2πR and the tracking mode of distal action will be favored when L &lt; 2πR. The time required for the distal action will be minimum when L = 2πR where the typical value of R for the binding of histones will beR ∼ 16 bps and L ∼ 102 bps. It seems that the free energy associated with the binding of the transcription factor with its cis-acting element and the distance of this cis-acting element from the corresponding promoter of the gene of interest is negatively correlated. Our results suggest that the looping and tracking modes of distal action are concurrently operating on the transcription activation and the physics that determines the timescales associated with the looping/tracking in the mechanism of action of these transcription factors on the initiation of the transcription event must put a selection pressure on the distribution of the distances of cis-regulatory modules from their respective promoters of the genes. The computational analysis of the upstream sequences of promoters of various genes in the human and mouse genomes for the presence of putative cisregulatory elements for a set of known transcription factors using the position weight matrices available with the JASPAR database indicates the presence of cis-acting elements with maximum probability at a distance of ∼102 bps from the promoters which substantiates our theoretical predictions. © 2010 IOP Publishing Ltd.

Journal of Physics A: Mathematical and Theoretical

Theory on the mechanism of distal action of transcription factors: Looping of DNA versus tracking along DNA

Proceedings of the National Academy of Sciences

Facilitated diffusion with DNA coiling

Optimal Feedback Strength for Noise Suppression in Autoregulatory Gene Networks

FEBS Letters

Robustness analysis of cellular memory in an autoactivating positive feedback system

On the minimization of fluctuations in the response times of autoregulatory gene networks

Journal	Biophysical Journal
ISSN	00063495
Open Access	No