TGFbeta inhibits serum shock-induced synchronization of circadian transcription by rewiring 3D chromatin crosstalk
Diettrich M.L.C., Scholz A.B., Tzelepis I., Martino M., Sifakis E.G., Sumida N., Walczak A., Zhao H., Ronnegren A.L., Imreh M., and Göndör A*
Karolinska Institute, MTC, Stockholm, Sweden
Circadian clocks generate cell-autonomous rhythms with 24-hour period length, which are built on intertwined transcriptional and translational feedback loops, and are reset by external time cues. Using assays that map circadian chromatin transitions in single cells, we have earlier uncovered that serum shock-induced synchronization of circadian transcription involves the oscillating recruitment of circadian loci to the repressive environment of the lamina, resulting in rhythmic transcriptional attenuation. This process is regulated by rhythmic complex formation between the genome organizers PARP1 and CTCF.Interestingly, TGFbeta resets the phase of circadian transcription via SMAD3 – a factor that interacts both with CTCF and PARP1. We have examined therefore, whether TGFbeta affects circadian rhythm by reprogramming 3D chromatin structures. Circular chromosome conformation capture data shows that TGFbeta treatment disassembled the 3D chromatin fibre interactome connecting circadian loci to lamina-associated domains (LADs). Moreover, in situ proximity ligation assay suggests that this effect of TGFbeta on chromatin crosstalk is mediated by the disruption of interactions between the genome organizers CTCF and PARP1. In line with the role of oscillating LAD-circadian gene interactions in rhythmic transcriptional attenuation, TGFbeta interfered with the synchronization of circadian transcription by serum shock at several clock-controlled genes in human embryoid bodies and MCF10A cells. Our results suggest that TGFbeta treatment and the consequent nuclear entry of SMAD3 disrupt CTCF-PARP1 interactions to perturb circadian 3D genome organization and oscillating transcription at loci regulated by CTCF-PARP1 interactions. “Zeitgebers” might thus reset the phase of circadian transcription by regulating the collaboration between the circadian clock and 3D genome organizers.
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