Competing targets of microRNA-608 affect anxiety and hypertension

Geula Hanin, Shani Shenhar-Tsarfaty, Nadav Yayon, Yau Yin Hoe, Estelle R. Bennett, Ella H. Sklan, Dabeeru C. Rao, Tuomo Rankinen, Claude Bouchard, Susana Geifman-Shochat, Sagiv Shifman, David S. Greenberg, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear.Wefound that changing a singlemiRNA-target interactioncansimultaneouslyaffect multiple othermiRNA-target interactionsandmodify physiological phenotype.Weshowthat 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.

Original languageEnglish
Article numberddu170
Pages (from-to)4569-4580
Number of pages12
JournalHuman molecular genetics
Issue number17
StatePublished - Sep 2014


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