Transcription-dependent mobility of single genes and genome-wide motions in live human cells

Nature Communications volume  15, Article number: 8879 (2024 ) Cite this article

The human genome is highly dynamic across all scales. At the gene level, chromatin is persistently remodeled and rearranged during active processes such as transcription, replication and DNA repair. At the genome level, chromatin moves in micron-scale domains that break up and re-form over seconds, but the origin of these coherent motions is unknown. Here, we investigate the connection between genomic motions and gene-level activity. Simultaneous mapping of single-gene and genome-wide motions shows that the coupling of gene transcriptional activity to flows of the nearby genome is modulated by chromatin compaction. A motion correlation analysis suggests that a single active gene drives larger-scale motions in low-compaction regions, but high-compaction chromatin drives gene motion regardless of its activity state. By revealing unexpected connections among gene activity, spatial heterogeneities of chromatin and its emergent genome-wide motions, these findings uncover aspects of the genome’s spatiotemporal organization that directly impact gene regulation and expression.

The spatio-temporal organizaton of the human genome plays a key role in all cellular processes, directly affecting the central dogma of biology1,2. While the static folding of the human genome has been revealed by chromosome conformation capture techniques3,4,5, it remains unclear how it evolves over time, especially at large length scales6,7,8. The mapping of real-time genome dynamics across an entire nucleus in live cells was recently accomplished by the displacement correlation spectroscopy (DCS)9. DCS uncovered that interphase chromatin exhibits two types of motion in the cell nucleus: a fast, local motion, consistent with single particle tracking studies10,11,12,13,14,15,16,17,18, and a slow, coherent motion, where micron-scale regions (3–5 μm) of chromatin move together for several seconds9. These two types of motion occur in the nucleus concurrently and superposed. The coherent motion has major implications for dynamical self-organization of the genome, enabling groups of genes to travel together for several seconds, although its biological function as well as the underlying biophysical mechanism(s) remain open questions.

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