Adams Nicholas M, Galitsyna Aleksandra, Tiniakou Ioanna, Esteva Eduardo, Lau Colleen M, Reyes Jojo, Abdennur Nezar, Shkolikov Alexey, Yap George S, Khodadadi-Jamayran Alireza, Mirny Leonid A, Reizis Boris
Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
bioRxiv. 2024 Oct 30:2024.09.18.613709. doi: 10.1101/2024.09.18.613709.
The cohesin protein complex extrudes chromatin loops, stopping at CTCF-bound sites, to organize chromosomes into topologically associated domains, yet the biological implications of this process are poorly understood. We show that cohesin is required for the post-mitotic differentiation and function of antigen-presenting dendritic cells (DCs), particularly for antigen cross-presentation and IL-12 secretion by type 1 conventional DCs (cDC1s) . The chromatin organization of DCs was shaped by cohesin and the DC-specifying transcription factor IRF8, which controlled chromatin looping and chromosome compartmentalization, respectively. Notably, optimal expression of IRF8 itself required CTCF/cohesin-binding sites demarcating the gene. During DC activation, cohesin was required for the induction of a subset of genes with distal enhancers. Accordingly, the deletion of CTCF sites flanking the gene reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin regulation in cell differentiation and function , and its bi-directional crosstalk with lineage-specifying transcription factors.
黏连蛋白复合物挤压染色质环，在与CTCF结合的位点处停止，从而将染色体组织成拓扑相关结构域，但这一过程的生物学意义仍知之甚少。我们发现，黏连蛋白是抗原呈递树突状细胞（DC）有丝分裂后分化和功能所必需的，特别是对于1型传统DC（cDC1）的抗原交叉呈递和IL-12分泌而言。DC的染色质组织由黏连蛋白和DC特异性转录因子IRF8塑造，它们分别控制染色质环化和染色体分区。值得注意的是，IRF8自身的最佳表达需要界定该基因的CTCF/黏连蛋白结合位点。在DC激活过程中，黏连蛋白是诱导具有远端增强子的一组基因所必需的。因此，基因侧翼CTCF位点的缺失会降低cDC1产生IL-12的能力。我们的数据揭示了黏连蛋白介导的染色质调控在细胞分化和功能中的重要作用，以及它与谱系特异性转录因子的双向相互作用。
