The compartmental polarization of interphase human chromosomes within the nucleus: A mechanism for transcriptional regulation of large chromosomes
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The structure and dynamics of individual chromosomes are significantly modulated by their local environment within the nucleus. It has long been established that heterochromatin (B compartment loci) associates with the lamina meshwork that lines the inner nuclear envelope. However, the extent to which these interactions perturb the chromosomal organization within a territory remains unclear. Using computer simulations and published imaging data, we further characterize the interaction between chromatin and the lamina and find striking consequences of lamina-association on the chromosomal structural ensemble. We find that lamina-associating chromosomes have their compartmentalization polarized in a direction perpendicular to the nuclear surface. Further, lamina-associated chromosomes exhibit shorter average distances between euchromatin loci (A compartment) than chromosomes without lamina contact. Energy landscape analysis of our simulations reveal that the sequestration of heterochromatin to the lamina allows for euchromatin to form more spatial contacts with other segments of euchromatin. The compaction of euchromatin due to lamina-association also diminishes the mobility of these regions. These findings suggest a mechanism for bringing together euchromatic segments that are separated by large genomic distances within a chromosome, potentially to share transcriptional machinery and enhance transcription for large chromosomes, which are often found at the nuclear periphery.
The structures of human chromosomes are highly dynamic and influenced by their local environment within the nucleus. A key environmental constraint is given by the nuclear membrane itself. The inner nuclear membrane is lined with protein filaments called the nuclear lamina, which directly interact with segments of inactive heterochromatin. We use published experimental imaging data combined with physics-based polymer models to investigate how lamina-association influences the three-dimensional organization of chromosomes. We find that the sequestration of inactive heterochromatin to the lamina promotes compaction of active euchromatin away from the lamina, similarly to allostery in proteins. Our results suggest that association with the nuclear periphery may enhance transcription by bringing actively transcribed regions into closer proximity, potentially facilitating the sharing of transcriptional machinery and splicing factors.
