MiR-137

Last updated
miR-137
MiR-137 secondary structure.png
miR-137 microRNA secondary structure and sequence conservation
Identifiers
Symbolmir-137
Rfam RF00694
miRBase family MIPF0000106
NCBI Gene 406928
HGNC 31523
Other data
RNA type microRNA
Domain(s) Eukaryota; Metazoa;
PDB structures PDBe

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.

Contents

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.

See also

Related Research Articles

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

mir-129 microRNA precursor family

The miR-129 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. This microRNA was first experimentally characterised in mouse and homologues have since been discovered in several other species, such as humans, rats and zebrafish. The mature sequence is excised by the Dicer enzyme from the 5' arm of the hairpin. It was elucidated by Calin et al. that miR-129-1 is located in a fragile site region of the human genome near a specific site, FRA7H in chromosome 7q32, which is a site commonly deleted in many cancers. miR-129-2 is located in 11p11.2.

mir-92 microRNA precursor family

The miR-92 microRNAs are short single stranded non-protein coding RNA fragments initially discovered incorporated into an RNP complex with a proposed role of processing RNA molecules and further RNP assembly. Mir-92 has been mapped to the human genome as part of a larger cluster at chromosome 13q31.3, where it is 22 nucleotides in length but exists in the genome as part of a longer precursor sequence. There is an exact replica of the mir-92 precursor on the X chromosome. MicroRNAs are endogenous triggers of the RNAi pathway which involves several ribonucleic proteins (RNPs) dedicated to repressing mRNA molecules via translation inhibition and/or induction of mRNA cleavage. miRNAs are themselves matured from their long RNA precursors by ribonucleic proteins as part of a 2 step biogenesis mechanism involving RNA polymerase 2.

<span class="mw-page-title-main">O-6-methylguanine-DNA methyltransferase</span> Mammalian protein found in Homo sapiens

O6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the O6-methylguanine DNA methyltransferase (MGMT) gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

mir-126

In molecular biology mir-126 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms.

mir-143 RNA molecule

In molecular biology mir-143 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. mir–143 is highly conserved in vertebrates. mir-143 is thought be involved in cardiac morphogenesis but has also been implicated in cancer.

mir-200

In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR-200c, miR-141, and miR-429. There is growing evidence to suggest that miR-200 microRNAs are involved in cancer metastasis.

miR-203

In molecular biology miR-203 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, such as translational repression and Argonaute-catalyzed messenger RNA cleavage. miR-203 has been identified as a skin-specific microRNA, and it forms an expression gradient that defines the boundary between proliferative epidermal basal progenitors and terminally differentiating suprabasal cells. It has also been found upregulated in psoriasis and differentially expressed in some types of cancer.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

In molecular biology mir-345 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

In molecular biology mir-885 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.

Melanoma is a rare but aggressive malignant cancer that originates from melanocytes. These melanocytes are cells found in the basal layer of the epidermis that produce melanin under the control of melanocyte-stimulating hormone. Despite the fact that melanoma represents only a small number of all skin cancers, it is the cause of more than 50% of cancer-related deaths. The high metastatic qualities and death rate, and also its prevalence among people of younger ages have caused melanoma to become a highly researched malignant cancer. Epigenetic modifications are suspected to influence the emergence of many types of cancer-related diseases, and are also suspected to have a role in the development of melanoma.

Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation. DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

<span class="mw-page-title-main">MIR124-3</span>

MicroRNA 124-3 is a protein that in humans is encoded by the MIR124-3 gene.

References

  1. 1 2 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. 1 2 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. 1 2 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. 1 2 3 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. S2CID   25440341.
  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. S2CID   41240512.
  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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.