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.

IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry

“…Besides that, the level of this transcription factor is inversely correlated with the levels of DNA methylation [48]. CTCF in partnership with cohesion molecules is also important in many immunological pathways, such as interferon gamma production in Th1 cells and establishment and maintenance of regulatory T cells in visceral adipose tissue and skeletal muscle [49,50]. In this scenario, we speculate that the increased quantity of antibodies against EBNA6_0488 results in a cross-reactive antibody response to the CTCF peptide, thus, reducing the abundance of this transcription factor.…”

Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum

“…CdLS patients typically show pre- and post-natal growth retardation, intellectual disability, developmental delay, limb anomalies, and a characteristic craniofacial appearance including thick eyebrows, synophrys, a short nose with an upturned nasal tip, a long and smooth philtrum, and a thin upper lip ( Kline et al, 2007 ; Kline et al, 2018 ). The majority of CdLS cases are caused by variants in the cohesin regulator NIPBL ( Parenti and Kaiser, 2021 ; Chandrasekaran et al, 2022 ) with 15% of them predicted to affect splicing ( Mannini et al, 2013 ). Noteworthy, mosaic variants are frequently (15%–20%) seen in individuals with a clinical diagnosis of CdLS ( Krawczynska et al, 2018 ).…”

“…CdLS patients are small in size and have a characteristic facial appearance including thick eyebrows, synophrys, a short nose with an upturned nasal tip, a long and smooth philtrum and a thin upper lip ( Kline et al, 2018 ). The majority of CdLS cases is caused by variants in NIPBL ( Chandrasekaran et al, 2022 ) with 15% of them predicted to affect splicing ( Mannini et al, 2013 ). Interestingly, somatic mosaicism is frequently (15%–20%) seen in individuals with classic features of CdLS ( Krawczynska et al, 2018 ).…”

IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry

“…In addition, the level of this transcription factor is inversely correlated with the levels of DNA methylation [71]. CTCF in partnership with cohesion molecules is also important in many immunological pathways, such as the interferon gamma production in Th1 cells and the establishment and maintenance of regulatory T cells in visceral adipose tissue and skeletal muscle [72,73]. In this scenario, we speculate that the increased quantity of antibodies against EBNA6_0488 results in a cross-reactive antibody response to the CTCF peptide, thus reducing the abundance of this transcription factor.…”