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Regulatory architecture of the RCA gene cluster captures a novel intragenic boundary and enhancer elements in B cells

ABSTRACT: The Regulators of Complement Activation (RCA) gene cluster comprises several tandemly arranged genes which share functions in the innate immune system. 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 important immunomodulatory region. Using 4C-seq, we captured extensive CTCF-mediated chromatin looping across the RCA gene cluster in B cells and showed these were organised into two topological associated domains (TADs). Interestingly, the 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 uncovered an intergenic enhancer and functionally demonstrated this element upregulates two RCA members (CR2 and CD55) in B cells simultaneously. Here, we highlight novel, long-range mechanisms whereby SLE susceptibility may be influenced by genetic variants, and the important contribution of chromatin topology to gene regulation and complex genetic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140127 | GEO | 2022/06/09

REPOSITORIES: GEO

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