Scaling laws of human transcriptional activity

Each human chromosome maintains its individuality during the cell cycle, and occupies a spatially limited volume, termed chromosome territory. Each linear chromosomal DNA is folded into multiple loops in the three dimensional space, and further organized into densely packed heterochromatin, less dense euchromatin and nucleosome-free regions that are accessible for transcription factor binding. As the average density of chromatin in the nucleus is very high, size exclusion potentially restricts access of large macromolecules such as RNA polymerase II and Mediator to DNA buried in chromosomal interiors. To examine this idea, we investigated whether increase in chromosome size leads to relative decrease in transcriptional activity of larger chromosomes. We found that the scaling of gene expression relative to chromosome size follows exactly the surface-area-to-volume ratio, suggesting that active genes are located at chromosomal surfaces. To directly test this hypothesis, we developed scalable fluorescent and genomic probes to assess chromatin accessibility to macromolecules of different sizes. We show that at the chromosomal level, open chromatin landscapes of small and large macromolecules are strikingly similar. However, dense chromatin is less accessible to large macromolecules. At a finer locus level, regions accessible to small transcription factors were primarily enriched around promoters, whereas regions accessible to large macromolecules were dispersed along gene bodies. Collectively, our results indicate that DNA accessibility is controlled at two different scales, and suggest that making chromatin accessible to large macromolecules is a critical step in the control of gene expression.