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Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFNγ signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.

Interferon-gamma (IFNg) producing T cells develop metabolic adaptation required for their effector functions in tumour biology, autoimmunity and antiviral defence. Using sorted CD4+ cells we demonstrated that glycolytic switch and high glucose uptake in IFNgproducing cells was associated with survivin expression. Inhibition of survivin restored glycolysis by upregulating the transcription of phosphofructokinase PFKFB3 and reducing glucose uptake. Integration of the whole-genome sequencing of the chromatin immunoprecipitated with survivin with transcription changes in CD4+ cells after survivin inhibition revealed co-localization of survivin, IRF1 and SMAD3 in the regulatory elements paired to the differentially expressed genes. Western blot demonstrated direct binding of survivin to IRF1 and SMAD3. Functionally, inhibition of survivin repressed IFNg signalling and activated SMAD3-dependent protein remodelling, which resulted in the effector-to-memory transition of CD4+ cells. These findings demonstrate the key role of survivin in IFNg-dependent metabolic adaptation and identify survivin inhibition as an attractive strategy to counteract these effects.

Survivin is a small protein that belongs to the inhibitor of apoptosis protein family and participates in cell division and apoptosis. It was actively studied in human cancers, inflammatory diseases and in autoimmune diseases. Here, we reveal that survivin takes part in epigenetic gene silencing by interaction with the polycomb repressive complex 2 (PRC2). PRC2 silences gene expression through tri-methylation of lysine 27 on histone 3 (H3K27). We detected differential expression of PRC2 core subunits in CD4+T cells with different survivin expression. ChIP-seq experiments indicated that survivin binds chromatin that overlap with the regions occupied by PRC2. ChIP-seq of H3K27 in CD4+T cells indicate that inhibition of survivin leads to a substantial increase in H3K27 tri-methylation by PRC2 in contrast to other histone modifications, which lends support to that survivin prevents PRC2 from functioning. Survivin binds peptides derived from PRC2 subunits Ezh2, EED, Suz12 and Jarid2 in a peptide microarray that cover intersubunit interfaces, catalytic residues, and present binding sites for substrates, DNA, and regulatory proteins. Amino acid composition of the peptides has substantial predictive power for survivin interaction in the peptide microarray as determined by multilayer perceptron classification analysis. NMR experiments with 15N labelled survivin indicate that peptide colocalization does not entirely depend on binding mediated by short range interactions. These results indicate that survivin interacts with PRC2, preventing the methylation of H3K27 and specific gene silencing.

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