Regulatory Architecture of the RCA Gene Cluster Captures an Intragenic TAD Boundary, CTCF-Mediated Chromatin Looping and a Long-Range Intergenic Enhancer.

Autor:	Cheng J; School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia., Clayton JS; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.; Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia., Acemel RD; Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Sevilla, Spain., Zheng Y; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.; Department of Statistics, University of Wisconsin-Madison, Madison, WI, United States., Taylor RL; Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.; Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia., Keleş S; Department of Statistics, University of Wisconsin-Madison, Madison, WI, United States.; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States., Franke M; Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Sevilla, Spain., Boackle SA; Department of Medicine, Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States., Harley JB; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.; US Department of Veterans Affairs Medical Centre, US Department of Veterans Affairs, Cincinnati, OH, United States., Quail E; School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.; School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia., Gómez-Skarmeta JL; Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Sevilla, Spain., Ulgiati D; School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jun 13; Vol. 13, pp. 901747. Date of Electronic Publication: 2022 Jun 13 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.901747
Abstrakt:	The Regulators of Complement Activation (RCA) gene cluster comprises several tandemly arranged genes with shared functions within the immune system. RCA members, such as complement receptor 2 ( CR2 ), are well-established susceptibility genes in complex autoimmune diseases. Altered expression of RCA genes has been demonstrated at both the functional and genetic level, but the mechanisms underlying their regulation are not fully characterised. We aimed to investigate the structural organisation of the RCA gene cluster to identify key regulatory elements that influence the expression of CR2 and other genes in this immunomodulatory region. Using 4C, we captured extensive CTCF-mediated chromatin looping across the RCA gene cluster in B cells and showed these were organised into two topologically associated domains (TADs). Interestingly, an inter-TAD boundary was located within the CR1 gene at a well-characterised segmental duplication. Additionally, we mapped numerous gene-gene and gene-enhancer interactions across the region, revealing extensive co-regulation. Importantly, we identified an intergenic enhancer and functionally demonstrated this element upregulates two RCA members ( CR2 and CD55 ) in B cells. We have uncovered novel, long-range mechanisms whereby autoimmune disease susceptibility may be influenced by genetic variants, thus highlighting the important contribution of chromatin topology to gene regulation and complex genetic disease. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Cheng, Clayton, Acemel, Zheng, Taylor, Keleş, Franke, Boackle, Harley, Quail, Gómez-Skarmeta and Ulgiati.)
Databáze:	MEDLINE
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