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Human renin gene (REN) gene-gene interactions and how breakdown of insulators bordering topologically associated domains might contribute to diverse diseases of ageing

Timothy Donlon (1, 2, 3) and Brian Morris (1, 4, 5)

  1. Honolulu Heart Program/Honolulu-Asia Aging Study, Department of Research, Kuakini Medical Center, Honolulu, Hawaii, USA

  2. Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA

  3. Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA

  4. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA

  5. Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia


Gene-gene interactions may contribute to complex polygenic disease aetiology. The human renin gene (REN) is of particular interest because aberrant expression can affect blood pressure, as well as cardiovascular and other diseases of ageing.


To determine interactions between REN and its neighbouring genes and genes genome-wide, compare tissue-specific expression of these, evaluate gene topography, and make predictions about breakdown of topologically associated domain (TAD) insulators with ageing.


The WashU Epigenome Browser public database and the Chromatin Space Interaction (CCSI) website were used to determine contact points for interactions. The CCSI database contains 91 sets of chromosomal three-dimensional (3D) data collected from published literature, the University of California Santa Cruz (UCSC) database, and the NCBI Gene Expression Omnibus (GEO) database, that has resulted in a total of 3,017,962 pairwise interactions.


We found that the REN promoter was connected via RNA polymerase II binding to its 12 neighbouring genes over a distance of 762,497 bp. These genes formed clusters bounded by CTCF-binding sites that insulate them from their gene neighbours. The genes formed 3 TADs, as follows: TAD1: ZC3H11A, SNRPE, LINC00303, SOX13; TAD2: ETNK2, REN, KISS1, GOLT1A; TAD3: PLEKHA6, LINC00628, PPP1R15B, PIK3C2B and MDM4. REN in TAD2 was isolated from its neighbouring 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. Genome-wide, REN was also connected with 62 distant genes, including the angiotensin II type 1 receptor gene, AGTR1.


Conceptually novel data revealed direct interactions between the REN promoter and its 12 immediate gene neighbours. The unique findings provide valuable insight into the broad role that renin plays in multiple aging-related conditions. We propose that as insulators bordering the TADs break down with age the 2 super-enhancers in the REN interactome modulate, and inappropriately allow expression of, REN and these co-compartmentalized genes in a wider spectrum of tissues, contributing to immune system dysregulation, cardiovascular disease and cancers.