1. Chromatin folding

The recognition of the intimate connection between the 3D genomic structure and gene expression has made chromatin folding a rapidly developing field with what used to be viewed as "well-accepted" concepts being continuously challenged by new experimental discoveries. Despite extensive study, many fundamental questions remained to be addressed such as the high-order genomic structure in single cells, the folding and regulatory mechanisms of the chromatin machinery, as well as its response to environmental changes. As an alternative to the classical textbook view of chromatin folding involving hierarchical fibers, we have recently developed a “3D forest” model of chromatin which predicts that chromatin is organized into a series of tree-like functional modules connected by a transcriptionally active backbone (DOI: 10.1126/sciadv.aay4055). Being able to reconcile the apparent conflict between the high packing heterogeneity and frequent long-range interactions of chromatin, the “3D forest” model provides new insights into the genomic structure at the single-cell level (NIH Director’s Blog: A new view of the 3D genome). Based on this new picture, we are developing more comprehensive chromatin models that allow us to better understand the dynamics of the 3D genome as well as the difference between normal and pathological chromatin folding.

2. Phase separation

Phase separation is an old concept in chemical physics and a new frontier in biology. Under certain conditions, many biopolymers can separate into condensed and dilute phases. However, biological condensates are complex as they involve multiple components and are sensitive to many physiochemical factors. Theoretical insights are urgently needed for the development of this new field. We use self-consistent mean field theory, molecular dynamics and dissipative particle dynamics to study the phase separation of different biopolymers, including intrinsically disordered proteins, lnc RNA, and chromatin. Our recent work highlights the importance of the interplay between different nonbonded interactions in shaping the biological phase separation down to nanoscale (https://doi.org/10.1016/j.bpj.2019.11.024). We are conducting systematic study to understand the effect of biopolymer sequences on their phase separation. We are also interested in how topological constraints influence microscopic phase separation such as the patterning of polymer-grafted surfaces.

3. Design of smart soft materials

From a materials point of view, biological systems are largely made of smart soft materials that are responsive to external stimuli. Inspired by nature, a large collection of bionic soft materials has been designed and fabricated in recent years, mostly based on polymers. Because of their excellent and finely tuned physicochemical properties, these novel soft materials have been widely used in the fields of biomedicine and biotechnology, electronic devices, and intelligent manufacturing. The study of bioinspired soft materials, which is a developing material discipline, involves the multidiscipline crossover of bionics, physics, chemistry, and biology. We use a combination of computational methods including computer simulations and machine learning to guide the rational design of smart soft materials for artificial systems.