Competing targets of microRNA-608 affect anxiety and hypertension.
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.
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.
Geula
G
Hanin
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.
Shani
S
Shenhar-Tsarfaty
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.
Nadav
N
Yayon
Yin Hoe
YH
Yau
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Avenue, 637551, Singapore.
Yau Yin
YY
Hoe
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.
Estelle R
ER
Bennett
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Ella H
EH
Sklan
Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Dabeeru C
DC
Rao
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
Tuomo
T
Rankinen
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
Claude
C
Bouchard
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Avenue, 637551, Singapore.
Susana
S
Geifman-Shochat
The Silberman Institute of Life Sciences and.
Sagiv
S
Shifman
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.
David S
DS
Greenberg
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.
Hermona
H
Soreq
D000110:Acetylcholinesterase / Q000235:genetics; D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001483:Base Sequence; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D064368:Healthy Volunteers; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011323:Primates / Q000235:genetics; D013045:Species Specificity; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D015850:Interleukin-6; C000591804:MIRN608 microRNA, human; D035683:MicroRNAs; D000110:Acetylcholinesterase; D020764:cdc42 GTP-Binding Protein; D006854:Hydrocortisone