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microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration

Fig 2

(A) Schematic complementarity map for a micro RNA-34a-TREM2 mRNA-3’-untranslated region (hsa-miRNA-34a-TREM2-mRNA-3’UTR) interaction between primary gene products on chromosome 1 and 6 [12]; human sequences shown; not drawn to scale; (B) hsa-miRNA-34a, encoded chr1p36.15 contains 3 canonical NF-kB sites (N) in the upstream promoter ( [8,12,56];; E1 = exon 1; E2 = exon 2 of the miRNA-34a gene; miRNA-34a expression is known to be NF-kB-sensitive in human brain cells [12,58]; (C) miRNA-34a precursor is processed into a mature 22 nucleotide hsa-miRNA-34a sequence; the free energy of association (EA) between hsa-miRNA-34a and the TREM2 mRNA-3’UTR sequence is ~16.2 kcal/mol; the miRNA-34a seed sequence 3’-UGUGACGG-5’ is overlaid in yellow; the complementary TREM2-3’-UTR recognition (DNA) sequence 5’-ACACTGCT-3’ is overlaid in red; an ‘|’ indicates a full hydrogen bond between miRNA-34a and the TREM2-mRNA-3’UTR and a ‘:’ indicates a partial hydrogen bond; (D) the hsa-miRNA-34a recognition feature within the TREM2-3’UTR is located about midway in the 299 nucleotide (nt) TREM2-3’UTR; several other brain-enriched miRNAs located within the TREM2-3’UTR and may also affect TREM2 mRNA stability and regulate its expression; sequence structures in (B) and (D) are not drawn to scale; (E) TREM2 is encoded as a single copy gene at human chr6p21.1; the primary transcript is a 2.7k nt TREM2 mRNA ( with a half-life of about 20 hr [60]; it is noteworthy that the TREM2 gene has no strong NF-kB binding site within at least 11 kb of its transcription start site and NF-kB activation has no strong effects on TREM2 transcription (unpublished); single stranded ribonucleotide sequences and alignment derived using miRBASE algorithms (European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton UK; srv/microcosm/cgi-bin/targets/v5/ transcript_id = ENST00000 373113) [36,8,12,20,56,58].

Fig 2