Monitoring the three-dimensional motion of chromatin at single molecule resolution

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PROJECT SUMMARY The notion that the positions of chromosomal loci within the interphase nucleus are not static, but move, is not new. However, the mechanistic role of the chromatin motion is usually underestimated. In fact, the nanoscale motion of chromatin may modulate the interaction of DNA with regulatory molecules, including chromatin effectors, transcription factors and non-coding RNAs, thus impacting the global patterns of gene expression. Unfortunately, experimental evidence supporting an essential role of chromatin motion in these activities is sparse. Thus, it is unclear if changes in chromatin dynamics facilitate these biological processes or are simply consequences. The goal of this project is to quantify the chromatin motion throughout the mammalian nucleus and to explore its mechanistic role in genome functions. To this end, the proposed research combines multidisciplinary approaches to concentrate on the link of chromatin motion with epigenetic regulation, DNA damage, and transcription, with the ultimate goal to understand the causality from epigenetic modification to phenotypic gene expression. The proposed projects are listed as below, Project 1 Map the chromatin motion in 3D with nanometer resolution. We will heavily incorporate the data science approach into our innovative imaging system to optimize the toolbox of measuring the chromatin. The toolbox will include the data-driven 3D imaging system and data science supported image informatics software. Project 2 Investigate the link between chromatin motion and epigenetic modification and transcription. We will explore the reciprocal interactions between chromatin motion and epigenetic modifications as well as transcription, respectively. These experimental investigations can feed proper mathematical models, therefore to formalize the reaction network in chromatin remodeling and gene expression. Results generated from these projects have great potential to reveal fundamental links between chromatin motion and gene expression, which will transform our understanding of disease mechanism and facilitate the development of therapeutic intervention.