Molecular Mechanisms of Stochastic Chromatin Effector Interaction Dynamics

Chromatin effector proteins dynamically interact with post-translational modifications (PTMs) on histone proteins by employing specialized reader domains. Their recruitment by defined chromatin PTM patterns results in a biological outcome, e.g. activation or repression of a target gene. These effector-chromatin interactions are important epigenetic regulatory mechanisms and are crucial for development, viral latency, and, if disrupted, can precipitate many cancers.

The molecular mechanisms of histone PTM readout are poorly understood. The aim of this IPhD Project is to combine in vitro single molecule experiments and mathematical modeling to establish a theoretical framework allowing us to interpret effector-chromatin interaction dynamics and thus to quantitatively predict signaling outcomes.

We will start our analysis with heterochromatin protein 1 (HP1, a key component of the gene repression machinery), to understand the establishment of the transcriptionally silent chromatin state. Based on initial modeling and error estimates on parameters, we will identify further experiments designed to improve model robustness and predictive capabilities. This theoretical framework will yield fundamental information about multivalent interactions between chromatin effectors and epigenetic chromatin modifications.

In the second phase we will investigate active chromatin state establishment by studying the competition between HP1 and the transcription activator BET-bromodomain protein 4 (Brd4). Here, we will undertake iterative experiments and modeling to determine how different degrees of chromatin methylation and acetylation result in a switch from a heterochromatin state (associated with HP1) to a euchromatin state (associated with Brd4).

We expect such quantitative characterization to help integrate the chromatin node into quantitative models of signaling networks for systems biology studies.

Keywords: Epigenetic mechanisms, chromatin effector proteins, histone PTMs, single-molecule experiments, mathematical modeling