Alternative titles; symbols
HGNC Approved Gene Symbol: MIR196A1
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38) : 17:48,632,490-48,632,559 (from NCBI)
MicroRNAs (miRNAs), such as miRNA196, are phylogenetically widespread 18- to 25-nucleotide RNAs found in animals and plants. These small RNAs can regulate gene expression at the translational level through interactions with their target mRNAs.
Lagos-Quintana et al. (2003) identified miR196 as a 21mer expressed primarily in ovary.
miR196 is encoded at 3 paralogous locations in the A, B, and C mammalian HOX clusters, with miR196A1 at the HOXB cluster on chromosome 17q21-q22, miR196A2 (609687) at the HOXC cluster on 12q13, and miR196B (609688) at the HOXA cluster on 7p15-p14.2 (Lagos-Quintana et al., 2003; Lim et al., 2003).
Yekta et al. (2004) found that miR196 has extensive evolutionarily conserved complementarity to messages of HOXB8 (142963), HOXC8 (142970), and HOXD8 (142985). RNA fragments diagnostic of miR196-directed cleavage of HOXB8 were detected in mouse embryos. Cell culture experiments demonstrated downregulation of HOXB8, HOXC8, HOXD8, and HOXA7 (142950) and supported the cleavage mechanism for miR196-directed repression of HOXB8. Yekta et al. (2004) concluded that their results point to an miRNA-mediated mechanism for the posttranscriptional restriction of HOX gene expression during vertebrate development and demonstrate that metazoan miRNAs can repress expression of their natural targets through mRNA cleavage in addition to inhibiting productive translation.
Hornstein et al. (2005) showed that miR196 acts upstream of Hoxb8 (142963) and Sonic hedgehog (Shh; 600725) in vivo in the context of limb development, thereby identifying a previously observed but uncharacterized inhibitory activity that operates specifically in the hindlimb. Hypothesizing that the unknown hindlimb inhibitory activity might be mediated by a small silencing RNA, Hornstein et al. (2005) used a conditional knockout allele of Dicer (606241), a key enzyme required for producing functional miRNAs from their precursors, to test whether the inhibition of Hoxb8 induction by retinoic acid (RA) in hindlimb is relieved by the removal of Dicer activity. In Dicer mutant animal hindlimbs, RA induced the expression of Hoxb8. Loss of Dicer activity does not affect expression of other known patterning genes in the developing limb bud. Thus, the previously uncharacterized inhibitory activity is lost in the absence of Dicer. Hornstein et al. (2005) concluded that miR196 functions in a fail-safe mechanism to assure the fidelity of expression domains that are primarily regulated at the transcriptional level, supporting the idea that many vertebrate miRNAs may function as a secondary level of gene regulation. Hornstein et al. (2005) also observed that miR196 had an expression signal in the hindlimb that was 20-fold higher than that in the forelimb. This differential expression was confirmed by Northern blot analysis.
Using microarray, PCR, and complementarity analyses, Pedersen et al. (2007) identified 8 miRNAs that were rapidly upregulated in IFNB (IFNB1; 147640)-stimulated mouse and human liver cell lines that showed sequence complementarity to hepatitis C virus (HCV; see 609532), an RNA virus, but not to hepatitis B virus (HBV; see 610424), a DNA virus. Of the 8 upregulated miRNAs, miR196, miR296 (MIRN296; 610945), miR351 (MIRN351), miR431 (MIRN431; 611708), and miR448 (MIRN448; 300686) had anti-HCV activity, and miR196 and miR448 directly targeted HCV genomic RNA. IFNB stimulation downregulated miR122 (MIRN122A; 609582), a liver-specific miRNA essential for HCV replication. Pedersen et al. (2007) concluded that IFNA (IFNA1; 147660) and IFNB, a common treatment regimen for HCV infection, use cellular miRNA, at least in part, to combat viral infections.
Brest et al. (2011) demonstrated that the miRNA196 family of microRNAs is overexpressed in the inflammatory intestinal epithelium of individuals with Crohn disease (see IBD19, 612278) and downregulates the protective C allele of the common IRGM exonic synonymous SNP 313C-T (608212.0001), but not the risk-associated T allele. The authors showed that the subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of the CD-associated adherent invasive E. coli (AIEC) by autophagy. Brest et al. (2011) hypothesized that AIEC infection in individuals with miRNA196-dysregulated IRGM expression (313T carriers) leads to altered antibacterial activity of intestinal epithelial cells and abnormal persistence of Crohn disease-associated intracellular bacteria, with a substantial impact on the outcome of intestinal inflammation.
Cheng et al. (2013) reported the beneficial effects of miR196a on Huntington disease (HD; 143100) in cell, transgenic mouse models, and human induced pluripotent stem cells derived from 1 individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT (613004) and pathologic aggregates, accompanying the overexpression of miR196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathologic progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR196a also decreased HTT expression and pathologic aggregates when HD-iPSCs were differentiated into the neuronal stage. Cheng et al. (2013) postulated that mechanisms of miR196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, CREB protein pathways, and several neuronal regulatory pathways in vivo.
Brest, P., Lapaquette, P., Souidi, M., Lebrigand, K., Cesaro, A., Vouret-Craviari, V., Mari, B., Barbry, P., Mosnier, J.-F., Hebuterne, X., Harel-Bellan, A., Mograbi, B., Darfeuille-Michaud, A., Hofman, P. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nature Genet. 43: 242-245, 2011. [PubMed: 21278745] [Full Text: https://doi.org/10.1038/ng.762]
Cheng, P.-H., Li, C.-L., Chang, Y.-F., Tsai, S.-J., Lai, Y.-Y., Chan, A. W. S., Chen, C.-M., Yang, S.-H. miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models. Am. J. Hum. Genet. 93: 306-312, 2013. [PubMed: 23810380] [Full Text: https://doi.org/10.1016/j.ajhg.2013.05.025]
Hornstein, E., Mansfield, J. H., Yekta, S., Hu, J. K.-H., Harfe, B. D., McManus, M. T., Baskerville, S., Bartel, D. P., Tabin, C. J. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438: 671-674, 2005. [PubMed: 16319892] [Full Text: https://doi.org/10.1038/nature04138]
Lagos-Quintana, M., Rauhut, R., Meyer, J., Borkhardt, A., Tuschl, T. New microRNAs from mouse and human. RNA 9: 175-179, 2003. [PubMed: 12554859] [Full Text: https://doi.org/10.1261/rna.2146903]
Lim, L. P., Glasner, M. E., Yekta, S., Burge, C. B., Bartel, D. P. Vertebrate microRNA genes. Science 299: 1540 only, 2003. [PubMed: 12624257] [Full Text: https://doi.org/10.1126/science.1080372]
Pedersen, I. M., Cheng, G., Wieland, S., Volinia, S., Croce, C. M., Chisari, F. V., David, M. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919-922, 2007. [PubMed: 17943132] [Full Text: https://doi.org/10.1038/nature06205]
Yekta, S., Shih, I., Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594-596, 2004. [PubMed: 15105502] [Full Text: https://doi.org/10.1126/science.1097434]