Date
2021-03-26Journal
PLoS GeneticsPublisher
Public Library of ScienceType
Article
Metadata
Show full item recordAbstract
Complex age-associated phenotypes are caused, in part, by an interaction between an individual’s genotype and age. The mechanisms governing such interactions are however not entirely understood. Here, we provide a novel transcriptional mechanism-based framework–SNiPage, to investigate such interactions, whereby a transcription factor (TF) whose expression changes with age (age-associated TF), binds to a polymorphic regulatory element in an allele-dependent fashion, rendering the target gene’s expression dependent on both, the age and the genotype. Applying SNiPage to GTEx, we detected ~637 significant TF-SNP-Gene triplets on average across 25 tissues, where the TF binds to a regulatory SNP in the gene’s promoter or putative enhancer and potentially regulates its expression in an age- and allele-dependent fashion. The detected SNPs are enriched for epigenomic marks indicative of regulatory activity, exhibit allele-specific chromatin accessibility, and spatial proximity to their putative gene targets. Furthermore, the TF-SNP interaction-dependent target genes have established links to aging and to age-associated diseases. In six hypertension-implicated tissues, detected interactions significantly inform hypertension state of an individual. Lastly, the age-interacting SNPs exhibit a greater proximity to the reported phenotype/diseases-associated SNPs than eSNPs identified in an interaction-independent fashion. Overall, we present a novel mechanism-based model, and a novel framework SNiPage, to identify functionally relevant SNP-age interactions in transcriptional control and illustrate their potential utility in understanding complex age-associated phenotypes.Identifier to cite or link to this item
http://hdl.handle.net/10713/15084ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1009427
Scopus Count
Collections
Related articles
- Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter.
- Authors: Visser M, Palstra RJ, Kayser M
- Issue date: 2015 May 1
- An integrative functional genomics framework for effective identification of novel regulatory variants in genome-phenome studies.
- Authors: Zhao J, Cheng F, Jia P, Cox N, Denny JC, Zhao Z
- Issue date: 2018 Jan 29
- Co-regulated transcripts associated to cooperating eSNPs define Bi-fan motifs in human gene networks.
- Authors: Kreimer A, Pe'er I
- Issue date: 2014 Sep
- How to Use SNP_TATA_Comparator to Find a Significant Change in Gene Expression Caused by the Regulatory SNP of This Gene's Promoter via a Change in Affinity of the TATA-Binding Protein for This Promoter.
- Authors: Ponomarenko M, Rasskazov D, Arkova O, Ponomarenko P, Suslov V, Savinkova L, Kolchanov N
- Issue date: 2015
- A New Mechanism for Mendelian Dominance in Regulatory Genetic Pathways: Competitive Binding by Transcription Factors.
- Authors: Porter AH, Johnson NA, Tulchinsky AY
- Issue date: 2017 Jan