Abstract
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.
Highlights
Genomic content inside the nucleus exists at different levels of organization
We explored and summarized current knowledge connecting the proteins of cohesin complex with immune relevant processes and transcriptional activity in immune loci which has just started emerging
Cohesin proteins act at the intersection of major immune pathways including those mediated by NF-kB (RAD21), IL-6 (STAG1, SGO1, RAD21) and IFNg (RAD21, STAG2)
Summary
Genomic content inside the nucleus exists at different levels of organization. A few of these levels are contact domains or topologically associating domains [1], chromosomal compartments [2], chromosomal loops [3, 4], phase-separation [5], and nucleosomes. The rise of chromatin conformation capture (3C) techniques directed the attention to hitherto unidentified functional properties of cohesin including its highly dynamic binding to DNA maintained by proteins CDC5A and WAPL [6], and its early loading on chromatin prior to the onset of S phase of the cell cycle through the NIPBL-MAU2 loader complex [7]. These observations emphasized unrecognized roles of cohesin in regulation of transcription, and 3D genome organization. This review explores recent emerging evidence on the role of cohesin in enabling long-range chromatin interactions and mediating multiple regulatory networks in cells of adaptive and innate immunity with potential implications in autoimmunity
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