2. Academic Validation
  3. Competing targets of microRNA-608 affect anxiety and hypertension

Competing targets of microRNA-608 affect anxiety and hypertension

  • Hum Mol Genet. 2014 Sep 1;23(17):4569-80. doi: 10.1093/hmg/ddu170.
Geula Hanin 1,  Shani Shenhar-Tsarfaty 1,  Nadav Yayon 1,  Yin Hoe Yau,  Estelle R Bennett 1,  Ella H Sklan 2,  Dabeeru C Rao 3,  Tuomo Rankinen 4,  Claude Bouchard 4,  Susana Geifman-Shochat 5,  Sagiv Shifman 6,  David S Greenberg 1,  Hermona Soreq 7
Affiliations

Affiliations

  • 1 The Silberman Institute of Life Sciences and The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel.
  • 2 Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • 3 Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  • 4 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • 5 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Avenue, 637551, Singapore.
  • 6 The Silberman Institute of Life Sciences and.
  • 7 The Silberman Institute of Life Sciences and The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 91904, Israel hermona.soreq@mail.huji.ac.il.
PMID: 24722204 DOI: 10.1093/hmg/ddu170
Abstract

MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects Others remained unclear. We found that changing a single miRNA-target interaction can simultaneously affect multiple Other miRNA-target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3'-untranslated region (3'UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of Other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.

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  • HY-12755
    99.87%, Cdc42 GTPase Inhibitor