Understanding the effect of transcriptional activity on chromatin dynamics

I provided a theoretical underpinning for the reduction in chromatin mobility with active transcription. There were experimental observations that chromatin mobility increases upon inhibiting transcription whereas ongoing transcriptional activity suppresses chromatin motion. This is a counter-intuitive finding because the actively transcribing RNA polymerase (RNAP) II exerts tension force on DNA which would make the gene region more open and dynamic. I elucidated the potential physical mechanism of this phenomenon, using a simple copolymer model capable of capturing the structural and dynamical properties of interphase chromosomes. By incorporating the biophysically relevant effect of transcription-induced active force, the model faithfully predicts the reduction in the mobilities of the active loci. The underlying mechanistic principle is that the active forces can induce a liquid-to-solid-like transition which leads to the collective suppression of the locus motion. This work has groundbreaking significance in the field since it successfully connects the chromosome organizational dynamics to its functional property, suggesting a novel insight into how transcription could shape the coexistence of fluid- and solid-like characters (light-blue spheres in the movie on the left) within chromosomes.

Shin et al., PNAS (2024)

From effective interactions extracted using experimental data to chromosome structures 

I developed a novel method that can extract effective chromosome interaction energies directly from an experimental contact map. The genome-wide chromosome conformation capture experiments, namely Hi-C, provided the contact frequencies of all the genomic locus pairs in various cell types for a number of species. Based on the concept of statistical potential, I created a simple method for extracting the effective interaction energies from the Hi-C data without any fitting procedure. I demonstrated that the simulations based on the inferred energy parameters faithfully reproduce the experimentally observed structural features of interphase chromosomes in both conventional and inverted nuclei. This parameter-free method is useful to not only characterize the effective interactions encoded in given experimental results on chromosome structures but also investigate the dynamics when used with polymer simulations. 

Shin et al., PRX Life (2023).

Entropic role of glycans in the binding of SARS-CoV-2 to the human receptor  

Since the COVID-19 pandemic, there have been extensive studies on the molecular mechanism of the invasion of SARS-CoV-2 into human cells, where glycans attached to either the virus spike protein or the receptor protein ACE2 are considered to mediate the viral invasion to some extent. In contrast to the prevalent belief that glycans mostly induce attractive interactions, my recent study highlighted the significant entropic contribution of ACE2 glycans to the binding with the virus protein. In the study, glycans were modeled as simple branched polymers on a three-dimensional lattice, whose monomer represents each sugar residue. Despite its simplicity, the model faithfully captured the change in the binding or dissociation constant upon specific glycosylation on ACE2. Currently I am following up on the water-mediated effective interactions between glycans using atomistic simulations. 

Mugnai, Shin, Thirumalai. Biophys. J. (2023).