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

  • Timothy A. Donlon
  • Brian J. MorrisEmail author
Research Article

Abstract

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.

Keywords

Aging Genomics Gene–gene interaction Topologically associated domains Diseases of aging Renin-angiotensin system Gene expression Longevity 

Abbreviations

AGTR1

Angiotensin II type 1 receptor

ChIA-PET

Chromatin immunoprecipitation paired-end tag sequencing

CTCF

CCCTC-binding factor zinc finger protein

RAS

Renin-angiotensin system

REN

Human renin gene

RNAPII

RNA polymerase II

TAD

Topologically associated domain

Notes

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

10522_2019_9834_MOESM1_ESM.docx (10.6 mb)
Supplementary material 1 (DOCX 10905 kb)

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of ResearchKuakini Medical CenterHonoluluUSA
  2. 2.Departments of Cell & Molecular Biology and PathologyUniversity of HawaiiHonoluluUSA
  3. 3.Department of Geriatric Medicine, John A. Burns School of MedicineUniversity of HawaiiHonoluluUSA
  4. 4.School of Medical Sciences and Bosch InstituteUniversity of SydneyCamperdownAustralia

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