Cap Analysis of Gene Expression Reveals Alternative Promoter Usage in a Rat Model of Hypertension

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2022 Jan 8

PMID 34996843

Authors

Sonal Dahale

Jorge Ruiz-Orera

Jan Silhavy

Norbert Hubner

Sebastiaan van Heesch

Michal Pravenec

Santosh S Atanur

Affiliations

Soon will be listed here.

Abstract

The role of alternative promoter usage in tissue-specific gene expression has been well established; however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites in the rat left ventricle, including 1,970 novel cardiac transcription start sites. We identified 28 genes with alternative promoter usage between SHR and Brown Norway, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5' UTR. We found that the shift in promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

References

Rintisch C, Heinig M, Bauerfeind A, Schafer S, Mieth C, Patone G . Natural variation of histone modification and its impact on gene expression in the rat genome. Genome Res. 2014; 24(6):942-53. PMC: 4032858. DOI: 10.1101/gr.169029.113. View

Petretto E, Mangion J, Dickens N, Cook S, Kumaran M, Lu H . Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet. 2006; 2(10):e172. PMC: 1617131. DOI: 10.1371/journal.pgen.0020172. View

Kunes J, Dobesova Z, Musilova A, Zidek V, Vorlicek J, Pravenec M . Hemodynamic characterization of recombinant inbred strains: twenty years later. Hypertens Res. 2008; 31(8):1659-68. DOI: 10.1291/hypres.31.1659. View

Carninci P, Kasukawa T, Katayama S, Gough J, Frith M, Maeda N . The transcriptional landscape of the mammalian genome. Science. 2005; 309(5740):1559-63. DOI: 10.1126/science.1112014. View

Howe K, Achuthan P, Allen J, Allen J, Alvarez-Jarreta J, Amode M . Ensembl 2021. Nucleic Acids Res. 2020; 49(D1):D884-D891. PMC: 7778975. DOI: 10.1093/nar/gkaa942. View

Pravenec M, Kren V, Landa V, Mlejnek P, Musilova A, Silhavy J . Recent progress in the genetics of spontaneously hypertensive rats. Physiol Res. 2014; 63(Suppl 1):S1-8. DOI: 10.33549/physiolres.932622. View

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

Durbin M, OKane J, Lorentz S, Firulli A, Ware S . SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects. Dev Biol. 2020; 464(2):124-136. PMC: 8257046. DOI: 10.1016/j.ydbio.2020.05.013. View

Dvir S, Velten L, Sharon E, Zeevi D, Carey L, Weinberger A . Deciphering the rules by which 5'-UTR sequences affect protein expression in yeast. Proc Natl Acad Sci U S A. 2013; 110(30):E2792-801. PMC: 3725075. DOI: 10.1073/pnas.1222534110. View

10.

Nutter C, Jaworski E, Verma S, Deshmukh V, Wang Q, Botvinnik O . Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes. Cell Rep. 2016; 15(10):2200-2213. PMC: 4899142. DOI: 10.1016/j.celrep.2016.05.002. View

11.

Atanur S, Diaz A, Maratou K, Sarkis A, Rotival M, Game L . Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell. 2013; 154(3):691-703. PMC: 3732391. DOI: 10.1016/j.cell.2013.06.040. View

12.

Jin J, Nakura J, Wu Z, Yamamoto M, Abe M, Tabara Y . Association of endothelin-1 gene variant with hypertension. Hypertension. 2003; 41(1):163-7. DOI: 10.1161/01.hyp.0000043680.75107.cf. View

13.

Yasuda H, Kamide K, Takiuchi S, Matayoshi T, Hanada H, Kada A . Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension. J Hum Hypertens. 2007; 21(11):883-92. DOI: 10.1038/sj.jhh.1002234. View

14.

Payankaulam S, Raicu A, Arnosti D . Transcriptional Regulation of , the Insulin Receptor Gene. Genes (Basel). 2019; 10(12). PMC: 6947883. DOI: 10.3390/genes10120984. View

15.

Kunes J, Kren V, Pravenec M, Zicha J . Use of recombinant inbred strains for evaluation of intermediate phenotypes in spontaneous hypertension. Clin Exp Pharmacol Physiol. 1994; 21(11):903-6. DOI: 10.1111/j.1440-1681.1994.tb02463.x. View

16.

Witte F, Ruiz-Orera J, Mattioli C, Blachut S, Adami E, Schulz J . A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion. Genome Biol. 2021; 22(1):191. PMC: 8240307. DOI: 10.1186/s13059-021-02397-w. View

17.

Aitman T, Critser J, Cuppen E, Dominiczak A, Fernandez-Suarez X, Flint J . Progress and prospects in rat genetics: a community view. Nat Genet. 2008; 40(5):516-22. DOI: 10.1038/ng.147. View

18.

Belfiore A, Malaguarnera R, Vella V, Lawrence M, Sciacca L, Frasca F . Insulin Receptor Isoforms in Physiology and Disease: An Updated View. Endocr Rev. 2017; 38(5):379-431. PMC: 5629070. DOI: 10.1210/er.2017-00073. View

19.

Materna S, Sinha T, Barnes R, van Bueren K, Black B . Cardiovascular development and survival require Mef2c function in the myocardial but not the endothelial lineage. Dev Biol. 2018; 445(2):170-177. PMC: 6370303. DOI: 10.1016/j.ydbio.2018.12.002. View

20.

Hubner N, Wallace C, Zimdahl H, Petretto E, Schulz H, Maciver F . Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet. 2005; 37(3):243-53. DOI: 10.1038/ng1522. View