In silico analysis of human renin gene-gene interactions and neighborhood topologically associated domains suggests breakdown of insulators contribute to ageing-associated diseases.

Three-dimensional chromatin architecture and gene-gene interactions impact gene expression. We assembled this information, in silico, for the human renin gene (REN). We searched for chromatin contacts and boundaries and the locations of super-enhancers that are involved in cell specific differentiation. The REN promoter was connected via RNA polymerase II binding to promoters of 12 neighboring genes on chromosome 1q32.1 over a distance of 762,497 bp. This constitutes a regulatory archipelago. The genes formed 3 topologically associated domains (TADs), as follows: TAD1: ZC3H11A, SNRPE, LINC00303; SOX13; TAD2: ETNK2, REN, KISS1, GOLT1A; TAD3: PLEKHA6, LINC00628, PPP1R15B, PIK3C2B, MDM4. REN in TAD2, was isolated from its neighboring genes in TAD1 and TAD3 by CTCF-binding sites that serve as insulators. TAD1 and TAD3 genes SOX13 and LINC00628 overlapped super-enhancers, known to reside near nodes regulating cell identity, and were co-expressed in various tissues, suggesting co-regulation. REN was also connected with 62 distant genes genome-wide, including the angiotensin II type 1 receptor gene. The findings lead us to invoke the following novel hypothesis. While the REN promoter is isolated from neighboring super-enhancers in most cells by insulators, these insulators break down with cell age to permit the inappropriate expression of REN in non-kidney cells by using the neighboring super-enhancers, resulting in expression in a wider spectrum of tissues, contributing to aging-related immune system dysregulation, cardiovascular diseases and cancers. Research is needed to confirm this hypothesis experimentally.