For bacteria, transcription regulation can increasingly be described on a quantitative level with theoretical models based on the biophysics of protein-DNA interactions. Our own previous work contributed to this development by characterizing physical [1] and evolutionary [2] constraints, devising “thermodynamic models” for combinatorial transcription logic [3, 5], analyzing time-dependent gene expression data from bulk [9] and single-cell [7] experiments, and studying functional [4] and evolutionary [8] design principles of bacterial gene regulation. By comparison, the current level of understanding of transcription regulation in eukaryotes is significantly less quantitative, even for the simplest model system, yeast. Attempts to transfer such biophysical modeling approaches from bacteria to yeast face a number of challenges. One important challenge is presented by the fact that eukaryotic transcription and its regulation occur in the context of chromatin. The positions of nucleosomes on a eukaryotic genome determine which parts of the DNA are readily accessible, e.g. for binding of transcription factors (TFs), and conversely, the binding of TFs also affects the positioning of nucleosomes. DNA accessibility is modulated by various chromatin remodeling complexes and histone modification enzymes, many of which are specifically recruited by transcription factors. The central goal of the project, building on previous work [6, 10] and to be pursued in close collaboration with the experimental group of Dr. Philipp Korber (LMU), is to physically disentangle various effective interactions that determine nucleosome positions in vivo and also in vitro. Such a physics-based description will contribute towards the larger scale effort in biology to unravel the interplay of transcription factors, the core transcription machinery, and chromatin, that ultimately results in the complexity of cis-regulatory gene regulation.

Patrick Hillenbrand

Brendan Osberg

Dr. Johannes Nübler

Möbius W, Osberg B, Tsankov AM, Rando OJ, Gerland U (2013). Toward a unified physical model of nucleosome patterns flanking transcription start sites. Proc Natl Acad Sci U S A 110(14):5719–24. 

[1] U. Gerland, J.D. Moroz, and T. Hwa (2002) Physical constraints and functional characteristics of Transcription Factor-DNA interaction. Proc. Natl. Acad. Sci. USA 99, 12105–10.

[2] U. Gerland and T. Hwa (2002) On the selection and evolution of regulatory binding motifs. J. Mol. Evol. 55, 386–400.

[3] N.E. Buchler, U. Gerland, and T. Hwa (2003) On schemes of combinatorial transcription logic. Proc. Natl. Acad. Sci. USA 100, 5136–5141.

[4] N.E. Buchler, U. Gerland, and T. Hwa (2005) Nonlinear protein degradation and the function of genetic circuits. Proc. Natl. Acad. Sci. USA 102, 9559–9564.

[5] L. Bintu, N.E. Buchler, H. Garcia, U. Gerland, T. Hwa, J. Kondev & R. Phillips (2005) Transcriptional regulation by the numbers: models. Curr. Opin. Genet. Dev. 15, 116-124

[6] W. Möbius, R. Neher, and U. Gerland (2006) Kinetic accessibility of buried DNA sites in nucleosomes. Phys. Rev. Lett. 97, 208102.

[7] J. Megerle, G. Fritz, U. Gerland, K. Jung, J. Rädler (2008) Timing and dynamics of single cell gene expression in the arabinose utilization system. Biophys. J. 95, 2103–2115.

[8] U. Gerland and T. Hwa (2009) Evolutionary selection between alternative modes of gene regulation. Proc. Natl. Acad. Sci. USA 106, 8841–8846.

[9] G. Fritz, C. Koller, K. Burdack, L. Tetsch, I. Haneburger, K. Jung, and U. Gerland (2009) Induction kinetics of a conditional pH stress response system in Escherichia coli. J. Mol. Biol. 393, 272–286.

[10] W. Möbius and U. Gerland (2010) Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites. PLoS Comp. Biol. 6, e1000891.