mir-137

In molecular biology, miR-137 (or microRNA-137) is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.

mir-137
miR-137 microRNA secondary structure and sequence conservation
Identifiers
Symbolmir-137
RfamRF00694
miRBase familyMIPF0000106
NCBI Gene406928
HGNC31523
Other data
RNA typemicroRNA
Domain(s)Eukaryota; Metazoa;
PDB structuresPDBe

Recent genome-wide association studies (GWAS) have provided evidence to suggest that single nucleotide polymorphisms in the vicinity of the MIR137 gene are statistically associated with schizophrenia and other psychiatric disorders.[1][2]

miR-137 is shown to regulate neural stem cell proliferation and differentiation in mouse embryonic stem cells, and neuronal maturation, including regulation of dendrite length, branch points, end points, and spine density in mouse adult hippocampal neuroprogenitor-derived and mouse fetal hippocampus neurons. Decreased spine density has also been observed in the dorsolateral cortex of patients with schizophrenia.

miR-137 belongs to the miR-137 clan (a clan is group of two or more RNA families that have arisen from a single evolutionary origin, as derived from their related structure and function). The miR-137 clan contains two members: miR-137 and miR-234; the total number of RNA domains in the clan is 112.

Chromosomal location and transcription

miR-137 is located on chromosome 1p22 within the non-protein-coding RNA gene AK094607.[3] It is transcribed as a non-coding primary miRNA (pri-miRNA) transcript, which is then processed into precursor miRNA (pre-miRNA) and finally into the mature and functional miRNA of 21 to 25 nucleotides. The mature miRNA functions by binding to the 3' untranslated region (3' UTR) of multiple target mRNAs. This binding in turn results in an inhibition of translation of the target protein or degradation of the target messenger RNA.

The post-transcriptional processing of microRNA-137 can be altered by presence of a 15-bp variable nucleotide tandem repeat in the primary miRNA transcript, which leads to change in folding and the secondary structure of miR-137. This alteration is believed to cause inefficient processing of miR-137 to its mature form, and serve as a mechanism to downregulate miR-137 expression in various human melanoma cell lines.

Expression pattern

miR-137 has been reported to be enriched in neurons. In particular, in situ hybridisation showed an enhanced expression of miR-137 within the dentate gyrus and the molecular layer of adult hippocampus, a region of the brain with significant plasticity and continuous production of new neurons.[4]

miR-137 is also found to be constitutively expressed in normal colonic epithelium in humans.[5]

Epigenetic regulation and cancers

miR-137 is embedded within a CpG island, a genomic region containing high frequency of CpG dinucleotides, and is reported to be frequently silenced by promoter hyper-methylation in many tumour types, including colorectal, gastric, breast and squamous cell carcinoma of the head and neck.[6][7][8]

miR-137 is epigenetically silenced in colorectal adenomatous tissues to the same extent as in colorectal cancer tissues, suggesting that methylation of miRNA is an early event in colorectal carcinogenesis.[5]

Analysis of promoter methylation in oral rinses of patients with squamous cell carcinoma of the head and neck showed that miR-137 methylation is associated with female gender and inversely associated with body mass index.[9] Furthermore, epigenetic alteration of miR-137 appears to be frequently detected in patients' oral rinses and may serve as a future biomarker in DNA methylation panels.

Targets

Several target genes of miR-137 have been documented and shown to play important roles in various human cancers, cell cycle signalling and mouse embryonic stem cell development.

Balaguer et al. identified a list of 32 genes targeted by miR-137 by cross-referencing the global gene expression analysis of HCT 116 colorectal carcinoma cells after transfection of miR-137 with the list of predicted miR-137 targets via miRecords database.[5] Among these targets, LSD1 (Lysine-specific histone demethylase 1A, also known as KDM1A) has been shown to be directly downregulated by miR-137 via binding to its 3'UTR. LSD1 is implicated in maintaining the undifferentiated phenotype of prostate cancer and neuroblastoma, thereby promoting tumour growth. It is thus postulated that miR-137 plays a tumour suppressive role by negatively modulating LSD1 protein expression.

Liu et al. further showed that miR-137 targets Cdc42 (cell division cycle 42), a well-known member of the Rho GTPase family found be upregulated in many human cancer types such as colorectal, testicular and breast cancers. In particular, the target site for miR-137 in the Cdc42 3' UTR is highly conserved across various species including human, chimpanzee, mouse, rat, dog and chicken. By inhibiting the Cdc42/PAK signalling pathway, miR-137 decreases proliferation, invasion and G0/G1 cell cycle progression of colorectal cancer cells.[10]

miR-137 has also been shown to directly inhibits CDK6 (Cyclin-dependent kinase 6) expression and decreases the level of phosphorylated RB (retinoblastoma), a known CDK6 downstream target. This is proposed to be the mechanism whereby miR-137 induces differentiation and inhibits proliferation of adult mouse neural stem cells, oligodendroma-derived stem cells, as well as human glioblastoma multiforme-derived stem cells.[11] In addition, miR-137 targets Mib1 (Mind Bomb-1), a ubiquitin ligase known to be important for neurogenesis and neurodevelopment.[4]

Another notable target of miR-137 is MITF (Micropthalmia Associated Transcription Factor), a master regulator of melanocyte development and function that is thought to be frequently misregulated in human melanomas.[3] It is proposed that miR-137 also acts as a tumour suppressor in melanoma cells by down-regulating both MITF and CDK6.[3][12]

In mouse embryonic stem cells (ESCs), Jarid1b (also known as KDM5b, a histone H3 Lysine 4 demethylase) has recently been shown to be another direct target of miR-137. Jarid1b is frequently expressed early in mouse embryonic development and is thought to maintain the expression of undifferentiated ESC markers. By suppressing Jarid1b protein level, miR-137 is believed to play a role in modulating the differentiated state of mouse ESCs.[13]

Stephan Ripke et al.[1] have identified fourteen target sites predicted by TargetScan:[14] C6orf47 (open reading frame of chromosome 6), HLA-DQA1 (Major histocompatibility complex, class II, DQ alpha 1), TNXB (A member of the tenascin family, also known as hexabrachion-like protein is a glycoprotein that is expressed in connective tissues including skin, joints and muscles) VARS (Valyl-tRNA synthetase), WBP1L (WW domain binding protein 1-like), CACNA1C (Calcium channel, voltage-dependent, L type, alpha 1C subunit), DPYD (Dihydropyrimidine dehydrogenase [NADP+]), CACNB2 (Voltage-dependent L-type calcium channel subunit beta-2), TSSK6 (Testis-Specific Serine Kinase 6), NT5DC2 (Cytosolic 5'-nucleotidase), PITPNM2 (Membrane-associated phosphatidylinositol transfer protein 2), SBNO1 (strawberry notch homolog 1), ZEB2 (Zinc finger E-box-binding homeobox 2) and PRKD3 (Serine/threonine-protein kinase D3).

Neault et al.[15] recently identified miR-137 as a senescence effector miRNA induced by oncogenic Ras. More specifically, miR-137 inhibits KDM4A, a histone lysine demethylase participating in gene repression and the bypass of oncogene-induced senescence in vivo.[16] KDM4A targets CHD5, a tumour suppressor and positive regulator p53 expression. It was observed that miR-137 expression is lost in Ras-dependent pancreatic cancer, and that restoration of its expression leads to cellular growth arrest and senescence in pancreatic cancer cells.

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See also

References
  1. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium; Sanders, Alan R; Kendler, Kenneth S; Levinson, Douglas F; Sklar, Pamela; Holmans, Peter A; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A; Andreassen, Ole A; Scolnick, Edward; Cichon, Sven; St. Clair, David; Corvin, Aiden; Gurling, Hugh; Werge, Thomas; Rujescu, Dan; Blackwood, Douglas H R; Pato, Carlos N; Malhotra, Anil K; Purcell, Shaun; Dudbridge, Frank; Neale, Benjamin M; Rossin, Lizzy; Visscher, Peter M; Posthuma, Danielle; Ruderfer, Douglas M; Fanous, Ayman; Stefansson, Hreinn; et al. (2011). "Genome-wide association study identifies five new schizophrenia loci". Nature Genetics. 43 (10): 969–76. doi:10.1038/ng.940. PMC 3303194. PMID 21926974.
  2. Cross-Disorder Group of the Psychiatric Genomics Consortium; Genetic Risk Outcome of Psychosis (GROUP) Consortium (2013). "Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis". The Lancet. 381 (9875): 1371–1379. doi:10.1016/S0140-6736(12)62129-1. PMC 3714010. PMID 23453885.
  3. Bemis LT, Chen R, Amato CM, Classen EH, Robinson SE, Coffey DG, Erickson PF, Shellman YG, Robinson WA (2008). "MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines". Cancer Res. 68 (5): 1362–8. doi:10.1158/0008-5472.CAN-07-2912. PMID 18316599.
  4. Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, Teng ZQ, Luo Y, Peng J, Bordey A, Jin P, Zhao X (2010). "MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase Mind Bomb-1". Stem Cells. 28 (6): 1060–70. doi:10.1002/stem.431. PMC 3140955. PMID 20506192.
  5. Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR, Goel A (2010). "Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis". Cancer Res. 70 (16): 6609–18. doi:10.1158/0008-5472.CAN-10-0622. PMC 2922409. PMID 20682795.
  6. Kozaki K; et al. (2008). "Exploration of tumour-suppressive microRNAs silenced by DNA hypermethylation in oral cancer". Cancer Res. 68 (7): 2094–2105. doi:10.1158/0008-5472.can-07-5194. PMID 18381414.
  7. Ando T; et al. (2009). "DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect". Int J Cancer. 124 (10): 2367–2374. doi:10.1002/ijc.24219. PMID 19165869.
  8. Vrba, L; Muñoz-Rodríguez, JL; Stampfer, MR; Futscher, BW (2013). "miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer". PLOS ONE. 8 (1): e54398. doi:10.1371/journal.pone.0054398. PMC 3547033. PMID 23342147.
  9. Langevin SM, Stone RA, Bunker CH, Grandis JR, Sobol RW, Taioli E (May 2010). "MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index". Carcinogenesis. 31 (5): 864–70. doi:10.1093/carcin/bgq051. PMC 2864416. PMID 20197299.
  10. Liu M, Lang N, Qiu M, Xu F, Li Q, Tang Q, Chen J, Chen X, Zhang S, Liu Z, Zhou J, Zhu Y, Deng Y, Zheng Y, Bi F (2010). "miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells". Int J Cancer. 128 (6): 1269–79. doi:10.1002/ijc.25452. PMID 20473940.
  11. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008). "miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells". BMC Med. 6: 14. doi:10.1186/1741-7015-6-14. PMC 2443372. PMID 18577219.
  12. Chen X, Wang J, Shen H, et al. (November 2010). "Epigenetics, MicroRNAs, and Carcinogenesis: Functional Role of MicroRNA-137 in Uveal Melanoma". Invest Ophthalmol Vis Sci. 52 (3): 1193–1199. doi:10.1167/iovs.10-5272. PMID 21051724.
  13. Tarantino C, Paolella G, Cozzuto L, et al. (September 2010). "miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells". FASEB J. 24 (9): 3255–63. doi:10.1096/fj.09-152207. PMID 20439489.
  14. Agarwal, Vikram; Bell, George W.; Nam, Jin-Wu; Bartel, David P. (2015-08-12). "Predicting effective microRNA target sites in mammalian mRNAs". eLife. 4: e05005. doi:10.7554/eLife.05005. ISSN 2050-084X. PMC 4532895. PMID 26267216.
  15. Neault, Mathieu; Mallette, Frédérick A.; Richard, Stéphane (2016-03-01). "miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells". Cell Reports. 14 (8): 1966–1978. doi:10.1016/j.celrep.2016.01.068. ISSN 2211-1247. PMID 26904954.
  16. Mallette, Frédérick A.; Richard, Stéphane (2012-11-29). "JMJD2A promotes cellular transformation by blocking cellular senescence through transcriptional repression of the tumor suppressor CHD5". Cell Reports. 2 (5): 1233–1243. doi:10.1016/j.celrep.2012.09.033. ISSN 2211-1247. PMID 23168260.

Further reading

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