The Rheumatoid Arthritis Risk Variant CCR6DNP Regulates CCR6 via PARP-1

Abstract

Understanding the implications of genome-wide association studies (GWAS) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. The non-coding triallelic dinucleotide polymorphism CCR6DNP is associated with risk for rheumatoid arthritis, and is considered likely causal because allelic variation correlates with expression of the chemokine receptor CCR6. Using transcription activator-like effector nuclease (TALEN) gene editing, we confirmed that CCR6DNP regulates CCR6. To identify the associated transcription factor, we applied a novel assay, Flanking Restriction Enhanced Pulldown (FREP), to identify specific association of poly (ADP-ribose) polymerase 1 (PARP-1) with CCR6DNP consistent with the established allelic risk hierarchy. Correspondingly, manipulation of PARP-1 expression or activity impaired CCR6 expression in several lineages. These findings show that CCR6DNP is a causal variant through which PARP-1 regulates CCR6, and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease.

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

“…First, during the life cycle of the coronavirus, PARP1 inhibitors may inhibit the viral growth through suppressing viral replication and impeding the binding of the nucleocapsid protein to viral RNAs [31,34,35,36], which can also be supported by our molecular docking results (see Section 2.6). Second, PARP1 inhibitors have been previously reported to play a critical role in regulating inflammatory response by modulating the expression of pro-inflammatory factors such as NF-κB, AP-1, IL-6 and downstream cytokines and chemokines [37,38,39,40]. Also, it has been shown that the overactivation of PARP1 promotes energy (NAD + /ATP) consumption and drives cell death, exacerbating the inflammation response [37,38,39,41].…”

“…Second, PARP1 inhibitors have been previously reported to play a critical role in regulating inflammatory response by modulating the expression of pro-inflammatory factors such as NF-κB, AP-1, IL-6 and downstream cytokines and chemokines [37,38,39,40]. Also, it has been shown that the overactivation of PARP1 promotes energy (NAD + /ATP) consumption and drives cell death, exacerbating the inflammation response [37,38,39,41]. PARP1 inhibitors thus may repress the NF-κB-mediated pro-inflammatory signals, and reduce energy failure and subsequent cell death induced by necrosis, thus providing a clinical potential for attenuating the cytokine storm and inflammatory response caused by SARS-CoV-2 infection.…”

“…The AutoGrid program was used to generate a grid map with 60×60×60 points spaced equally at 0.375Å for evaluating the binding energies between the protein and the ligands. The second possible pathway is to prevent the overactivation of PARP1 and thus avoid the depletion of NAD + and ATP, and the consequent cellular energy failure and cell death caused by necrosis [37,38,39,40]. (C).…”

“…The antiinflammation effects of PARP1 inhibitors may be achieved through two possible molecular pathways. The first one is to modulate the expression of pro-inflammation factors such as NF-κB, AP-1, IL-6 and downstream cytokines and chemokines[37,38,39,40].…”

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…In humans, an association between PARP-1 gene polymorphisms and RA was shown even if other studies reached contrasting conclusions [96,97]. A more recent study showed that a human RA-risk-associated non-coding polymorphism in the chemokine receptor CCR6 is a causal variant through which PARP-1 regulates CCR6 expression [98]. In gastric chronic inflammation induced by Helicobacter-specific T cell responses, PARP-1 sustains Th1 cell differentiation and the consequent T cell-driven immunopathology.…”