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

Frontiers in Immunology

John B. Harley³  Elizabeth Quail⁴  Rhonda L. Taylor⁵  Joshua S. Clayton⁵  José Luis Gómez-Skarmeta⁶  Martin Franke⁶  Rafael D. Acemel⁶  Sündüz Keleş⁷  Ye Zheng⁹  Susan A. Boackle^1,11  Daniela Ulgiati^1,12  Jessica Cheng^1,12 

[1] 0Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;1Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States;2US Department of Veterans Affairs Medical Centre, US Department of Veterans Affairs, Cincinnati, OH, United States;3School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia;Centre for Medical Research, The University of Western Australia, Crawley, WA, Australia;Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Sevilla, Spain;Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States;Department of Medicine, Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;Department of Statistics, University of Wisconsin-Madison, Madison, WI, United States;Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia;Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States;School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia;Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States;

关键词: RCA;    B cells;    enhancers;    chromatin looping;    TADs;   

DOI  :  10.3389/fimmu.2022.901747

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown