Novel Feedback loops between 3D Genome Organizers and the Circadian Clock regulate Rhythmic Chromatin Transitions in the Nuclear Architecture
Diettrich Mallet de Lima, C., Sifakis, E.G., Sumida, N., Scholz A. B., Martino, M., Tzelepis, I., Zhao, H., Ronnegren, A.L., Millán-Ariño, L., Walczak, A., Imreh, M., and Göndör, A.*
Karolinska Institute, Department of Microbiology, Tumor and Cell Biology, Stockholm, Sweden
Transcriptionally active and inactive chromatin domains tend to segregate into separate sub-nuclear compartments in the three-dimensional space of the nucleus. The spatial separation between active and inactive states likely promotes the robust maintenance of cell type-specific expression patterns and cellular phenotypes by reducing stochastic fluctuations in transcriptional activity. Using novel single-cell techniques that enable the simultaneous detection of chromatin states, transcription states and sub-nuclear localization of specific loci within the 3D space of the nucleus, we have found that serum shock-induced synchronization of circadian rhythm involves the coordinated and rhythmic recruitment of clock-controlled genes from transcriptionally permissive chromatin compartments to the repressive environment of the nuclear envelope. Localization of circadian genes to the lamina promotes the formation of transient inter-chromosomal chromatin fiber interactomes between circadian genes and repressed lamina-associated domains, which is followed by transcriptional attenuation and the subsequent release of clock-controlled genes from the lamina to the nuclear interior. We have, moreover, uncovered that rhythmic chromatin mobility between active and inactive chromatin environments and ensuing oscillations in transcriptional activity are regulated by novel feedback and feed-forward loops between the genome organizers PARP1 and CTCF, as well as members of the core clockwork. 3D genome organizers thus collaborate with the circadian clock machinery and the nuclear architecture to regulate the plasticity of oscillating 3D chromatin conformations and circadian transcription.