MicroRNA-138 is a potential regulator of memory performance in humans

abstract: ...Genetic factors underlie a substantial proportion of individual differences in cognitive functions in humans, including processes related to episodic and working memory. While genetic association studies have proposed several candidate memory genes, these currently explain only a minor fraction of the phenotypic variance. Here, we performed genome-wide screening on 13 episodic and working memory phenotypes in 1318 participants of the Berlin Aging Study II aged 60 years or older. The analyses highlight a number of novel single nucleotide polymorphisms (SNPs) associated with memory performance, including one located in a putative regulatory region of microRNA (miRNA) hsa-mir-138-5p (rs9882688, P -value = 7.8 10 9 ). Expression quantitative trait locus analyses on next-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines ( P -value = 5 10 4 ). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3 untranslated region (3 UTR) of DCP1B , a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3 UTR reporter constructs in two human cell lines (HEK293: P -value = 0.0470; SH-SY5Y: P -value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo . In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function.

...-generation RNA-sequencing data revealed that rs9882688 genotypes show a significant correlation with the expression levels of this miRNA in 309 human lymphoblastoid cell lines ( P -value = 5 10 4 ). In silico modeling of other top-ranking GWAS signals identified an additional memory-associated SNP in the 3 untranslated region (3 UTR) of DCP1B , a gene encoding a core component of the mRNA decapping complex in humans, predicted to interfere with hsa-mir-138-5p binding. This prediction was confirmed in vitro by luciferase assays showing differential binding of hsa-mir-138-5p to 3 UTR reporter constructs in two human cell lines (HEK293: P -value = 0.0470; SH-SY5Y: P -value = 0.0866). Finally, expression profiling of hsa-mir-138-5p and DCP1B mRNA in human post-mortem brain tissue revealed that both molecules are expressed simultaneously in frontal cortex and hippocampus, suggesting that the proposed interaction between hsa-mir-138-5p and DCP1B may also take place in vivo . In summary, by combining unbiased genome-wide screening with extensive in silico modeling, in vitro functional assays, and gene expression profiling, our study identified miRNA-138 as a potential molecular regulator of human memory function. genome-wide association study GWAS working memory episodic memory microRNA hsa-mir-138-5p DCP1B Introduction Interindividual variations of memory performance in humans are regulated by genetic and non-genetic factors. Early estimates from twin studies suggest that approximately half of the

..., 15 s at 95C, 60 s at 60C for overall 50 cycles. The reactions were run and visualized on a QuantStudio 12 K Flex Real-Time PCR System (Applied Biosystems). Assessment of mRNA expression levels Reverse transcription was performed using the High Capacity RNA-to-cDNA Kit (Applied Biosystems) on 0.2 g of total RNA following the manufacturer's instructions. The reactions were run on the Thermo Cycler PTC-240 (MJ Research, Waltham, MA, USA). Expression of the resulting DCP1B cDNA was assessed via PCR

... characterizing active regulatory elements (ENCODE Project Consortium et al., 2012 ). The second leading GWAS signal was elicited by SNP rs1016365, which is located approx. 6 kb 3 of EYA1 (Homo sapiens eyes absent homolog 1 [Drosophila]) a member of the eyes absent (EYA) family of proteins. The third best associated SNP in our GWAS (rs113948889) maps to an intron of DCP1B (encoding decapping mRNA 1B), which is a core component of the mRNA decapping complex, a key factor in the regulation of mRNA decay

... rs112215626, predicted to interfere with the binding of hsa-miR-4775 to the 3UTR of DCP1B mRNA (see miRNA-to-mRNA alignment in Figure 1A ). The second strongest effect was estimated for rs1044950, which was predicted to interfere with the binding of hsa-miR-138-5p to the 3 UTR of another DCP1B transcript (Figure 1B ). Interestingly, the same SNP is located within the coding sequence of alternative DCP1B transcripts where it is predicted to elicit an amino acid change from alanine to valine at the respective residues (i.e., Ala273Val, Ala249Val, Ala375Val; Supplementary Table 2 ). However, this missense substitution is not predicted to significantly alter protein function in any of the affected DCP1B transcripts (Supplementary Table 3 ) in silico based on estimates from PolyPhen2 (Adzhubei et al., 2010 ) or SIFT (URL: http://sift.bii.a-star.edu.sg/ ), indicating that the presumed effects on miRNA-to-mRNA binding may represent the overarching functional mechanism underlying the GWAS signal at this

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Gene: DCP1B - decapping mRNA 1B - (NCBI)

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