Abstract
MicroRNAs (miRNAs) are important gene regulators that are abundantly expressed in both the developing and adult mammalian brain. These non-coding gene transcripts are involved in post-transcriptional regulatory processes by binding to specific target mRNAs. Approximately one third of known miRNA genes are located within intronic regions of protein coding and non-coding regions, and previous studies have suggested a role for intronic miRNAs as negative feedback regulators of their host genes. In the present study, we monitored the dynamic gene expression changes of the intronic miR-338-3p and miR-338-5p and their host gene Apoptosis-associated Tyrosine Kinase (AATK) during the maturation of rat hippocampal neurons. This revealed an uncorrelated expression pattern of mature miR-338 strands with their host gene. Sequence analysis of the 3′ untranslated region (UTR) of rat AATK mRNA revealed the presence of two putative binding sites for miR-338-3p. Thus, miR-338-3p may have the capacity to modulate AATK mRNA levels in neurons. Transfection of miR-338-3p mimics into rat B35 neuroblastoma cells resulted in a significant decrease of AATK mRNA levels, while the transfection of synthetic miR-338-5p mimics did not alter AATK levels. Our results point to a possible molecular mechanism by which miR-338-3p participates in the regulation of its host gene by modulating the levels of AATK mRNA, a kinase which plays a role during differentiation, apoptosis and possibly in neuronal degeneration.
Highlights
MicroRNAs constitute a novel class of small 21–23 nucleotides long, non-coding RNAs that act as post-transcriptional regulators of gene expression
Previous reports have demonstrated that retinoic acid-mediated neuronal differentiation of human neuroblastoma cells results in the synchronized induction of expression levels of miR-338-3p and its host gene associated Tyrosine Kinase (AATK) [9]
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that 22 out of 74 pathways implicated the association of host genes, demonstrated significant over-representation of proteins encoded by the mRNA targets of associated intragenic miRNAs
Summary
MicroRNAs (miRNAs) constitute a novel class of small 21–23 nucleotides long, non-coding RNAs that act as post-transcriptional regulators of gene expression. They are highly conserved during evolution, and involved in a wide variety of biological processes. Most miRNAs are encoded in intergenic regions or within exonic loci, approximately one-third of the mammalian miRNA genes are located in introns of non-coding RNA genes, or within introns of protein-coding genes [6]. The precursor miR-338 sequence is intronically encoded within the Apoptosis-associated Tyrosine Kinase (AATK, known as AATYK) host gene [9]. This gene is upregulated during apoptosis of myeloid precursor cells induced by interleukin-3 deprivation [10,11], and in cultured cerebellar granule neurons undergoing apoptosis induced by exposure to a low K+ environment [12]
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