Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.

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The proprotein convertase subtilisin/kexin (PCSK) enzymes proteolytically convert immature proproteins into bioactive molecules and thereby they serve as key regulators of cellular homeostasis. The archetype PCSK, FURIN is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in T helper 1 type cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGFβ-1 in vivo, but FURIN’s role in cell-mediated immunity and Th polarization has remained elusive. Here, we show that T-cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4 receptor subunit alpha (IL-4Rα) on cell surface, sensitized IL-4/STAT6 signaling and a propensity to polarize towards the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass-spectrometry we further identify an association with a cytoskeleton modifying RAC/DOCK2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to down-regulate IL-4Rα cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T-cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance.

Background:The in vivo importance of PCSK7 in the vertebrates is currently poorly understood. Results: Inhibiting PCSK7 in zebrafish results in various developmental defects and dysregulation of gene expressions. Conclusion: PCSK7 is essential for zebrafish development and regulates the expression and proteolytic cleavage of TGF␤1a. Significance: PCSK inhibitors are considered future therapeutics for human diseases; understanding the biological role of PCSK7 is therefore critical.