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Novel microRNA regulators of atrial natriuretic peptide production

Wu, Connie; Arora, Pankaj; Agha, Obiajulu; Hurst, Liam A.; Allen, Kaitlin; Nathan, Daniel I.; Hu, Dongjian; Jiramongkolchai, Pawina; Smith, Gustav LU and Melander, Olle LU , et al. (2016) In Molecular and Cellular Biology 36(14). p.1977-1987
Abstract

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants... (More)

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.

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Molecular and Cellular Biology
volume
36
issue
14
pages
11 pages
publisher
American Society for Microbiology
external identifiers
  • scopus:84977669346
  • wos:000378924500007
ISSN
0270-7306
DOI
10.1128/MCB.01114-15
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English
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yes
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ef264ff7-58a5-406a-bdc1-49ba9cf9e779
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2017-02-08 14:15:59
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2017-09-18 11:37:34
@article{ef264ff7-58a5-406a-bdc1-49ba9cf9e779,
  abstract     = {<p>Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.</p>},
  author       = {Wu, Connie and Arora, Pankaj and Agha, Obiajulu and Hurst, Liam A. and Allen, Kaitlin and Nathan, Daniel I. and Hu, Dongjian and Jiramongkolchai, Pawina and Smith, Gustav and Melander, Olle and Trenson, Sander and Janssens, Stefan P. and Domian, Ibrahim and Wang, Thomas J and Bloch, Kenneth D. and Buys, Emmanuel S. and Bloch, Donald B. and Newton-Cheh, Christopher},
  issn         = {0270-7306},
  language     = {eng},
  number       = {14},
  pages        = {1977--1987},
  publisher    = {American Society for Microbiology},
  series       = {Molecular and Cellular Biology},
  title        = {Novel microRNA regulators of atrial natriuretic peptide production},
  url          = {http://dx.doi.org/10.1128/MCB.01114-15},
  volume       = {36},
  year         = {2016},
}