Abstract
G protein-coupled receptors are the principal mediators of the sweet, umami, bitter, and fat taste qualities in mammals. Intriguingly, the taste receptors are also expressed outside of the oral cavity, including in the gut, airways, brain, and heart, where they have additional functions and contribute to disease. However, there is little known about the mechanisms governing the transcriptional regulation of taste receptor genes. Following our recent delineation of taste receptors in the heart, we investigated the genomic loci encoding for taste receptors to gain insight into the regulatory mechanisms that drive their expression in the heart. Gene expression analyses of healthy and diseased human and mouse hearts showed coordinated expression for a subset of chromosomally clustered taste receptors. This chromosomal clustering mirrored the cardiac expression profile, suggesting that a common gene regulatory block may control the taste receptor locus. We identified unique domains with strong regulatory potential in the vicinity of taste receptor genes. We also performed de novo motif enrichment in the proximal promoter regions and found several overrepresented DNA motifs in cardiac taste receptor gene promoters corresponding to ubiquitous and cardiac-specific transcription factor binding sites. Thus, combining cardiac gene expression data with bioinformatic analyses, this study has provided insights into the noncoding regulatory landscape for taste GPCRs. These findings also have broader relevance for the study of taste GPCRs outside of the classical gustatory system, where understanding the mechanisms controlling the expression of these receptors may have implications for future therapeutic development.
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Abbreviations
- bHLH:
-
Basic helix-loop-helix
- bZIP:
-
Basic leucine zipper
- ChIP:
-
Chromatin immunoprecipitation
- ENCODE:
-
Encyclopedia of DNA elements
- GPCRs:
-
G protein-coupled receptors
- I/R:
-
Ischemia/reperfusion
- LAD:
-
Left anterior descending
- LV:
-
Left ventricular
- PWM:
-
Position weight matrix
- TAS1R/T1R:
-
Taste receptor type 1
- TAS2R/T2R:
-
Taste receptor type 2
- TFBS:
-
Transcription factor binding sites
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Acknowledgments
We gratefully acknowledge Dr Eric Olson (UT Southwestern Medical Center, Dallas, USA) for provision of mouse heart samples from experimental models of myocardial infarction and cardiac hypertrophy/heart failure. This work was supported by project grants awarded to WGT from the Australian National Health and Medical Research Council (NHMRC) (1024726) and the National Heart Foundation (NHF) of Australia (G-12B-6532). MR was supported by a Career Development Fellowship from the NHMRC and the NHF (1049980). SRF was supported by an Australian Postgraduate Award scholarship.
Authors’ contributions
SRF conceived of the study, participated in its design, performed and analyzed gene expression studies, and drafted the manuscript. EP participated in gene expression studies in mouse heart tissues. MS assisted with human heart sample preparation. NJS provided reagents and samples for human gene expression analyses. PM and CGR provided human myocardial tissues. WGT participated in the study design and coordination and helped to draft the manuscript. MR conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
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Foster, S.R., Porrello, E.R., Stefani, M. et al. Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation. Naunyn-Schmiedeberg's Arch Pharmacol 388, 1009–1027 (2015). https://doi.org/10.1007/s00210-015-1118-1
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DOI: https://doi.org/10.1007/s00210-015-1118-1