Transcription modulates chromatin dynamics and locus configuration sampling

G Forte and A Buckle and S Boyle and D Marenduzzo and N Gilbert and CA Brackley, NATURE STRUCTURAL & MOLECULAR BIOLOGY, 30, 1275-+ (2023).

DOI: 10.1038/s41594-023-01059-8

To study the dynamic 3D structure of specific loci, the authors combine a computer modeling scheme based on polymer physics with experimental validation. Their results indicate that chromatin dynamics are sufficiently fast to sample all possible locus conformations within minutes, generating wide dynamic variability within single cells. In living cells, the 3D structure of gene loci is dynamic, but this is not revealed by 3C and FISH experiments in fixed samples, leaving a notable gap in our understanding. To overcome these limitations, we applied the highly predictive heteromorphic polymer (HiP-HoP) model to determine chromatin fiber mobility at the Pax6 locus in three mouse cell lines with different transcription states. While transcriptional activity minimally affects movement of 40-kbp regions, we observed that motion of smaller 1-kbp regions depends strongly on local disruption to chromatin fiber structure marked by H3K27 acetylation. This also substantially influenced locus configuration dynamics by modulating protein-mediated promoter-enhancer loops. Importantly, these simulations indicate that chromatin dynamics are sufficiently fast to sample all possible locus conformations within minutes, generating wide dynamic variability within single cells. This combination of simulation and experimental validation provides insight into how transcriptional activity influences chromatin structure and gene dynamics.

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