Cohesin-Mediated Chromatin Interactions and Autoimmunity

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.

Keywords: CCCTC-binding factor; autoimmunity; cohesin; genome organization; immune signaling.

Figure 1

Cohesin complex enables chromatin architecture. (A) SMC1 and SMC3 heterodimer forms the ‘hinge’ region and the ATPase domains at either ends. RAD21 and STAG1/STAG2 complete the cohesin complex. Several proteins dynamically bind to the cohesin complex and regulate its function. Structure of cohesin complex was obtained from PDB ID 6wg3 (10). (B) Cognate binding sites of CTCF (in purple) constrain cohesin translocation, thus forming chromosomal loops. (C) Mechanistic models of cohesin action dynamically exist within a cell to enable cohesin-mediated chromatin organization. Figures were created using Chimera, Inkscape and the Servier Medical Art.

Figure 2

Cohesin complex involvement in T and B cell development. Cohesin-CTCF complex is important for successful transition through lymphocyte developmental stages. RAD21 and CTCF ensure proper TCR rearrangement by organizing distant V and J segments into close interacting networks. In B cells, RAD21 and SMC3 bind to specific BCR loci and regulate differentiation.

Figure 3

Functional enrichment analysis of the cohesin complex proteins. Experimentally confirmed protein-protein interactions for 22 proteins of the cohesin complex were retrieved from the BioGrid database. Functional enrichment analysis was done in Reactome. Immunologically relevant pathways (FDR p-value <10^-5) are presented on the right side and annotated to individual cohesin complex proteins by circled numbers corresponding to the immunologically relevant pathways. Number of interactors is shown next to each protein. Total number of interactors is indicated in black, immunologically relevant interactors are shown in red numbers.