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MEG3

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MEG3
Identifiers
AliasesMEG3, FP504, GTL2, LINC00023, NCRNA00023, PRO0518, PRO2160, prebp1, onco-lncRNA-83, maternally expressed 3 (non-protein coding), maternally expressed 3
External IDsOMIM: 605636; GeneCards: MEG3
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

55384

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Ensembl

ENSG00000214548

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UniProt

n
a

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RefSeq (mRNA)

NM_018514

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RefSeq (protein)

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Location (UCSC)Chr 14: 100.78 – 100.86 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

MEG3 (maternally expressed 3) is a maternally expressed, imprinted long non-coding RNA gene.[3]

Gene

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MEG3 is a genomically imprinted, maternally expressed long non-coding RNA (lncRNA) gene located within the DLK1-MEG3 imprinted locus on human chromosome 14q32.3, paired with the paternally expressed protein-coding gene DLK1 in the same domain.[4][5] The gene generates multiple alternatively spliced transcripts, all of which are non-coding, and is expressed across many normal tissues.[4]

At least 12 different isoforms of MEG3 are generated by alternative splicing.[6]

The non-Mendelian inheritance pattern, known as polar overdominance, likely results from the combination of the cis-effect on the expression levels of genes in the DLK1-GTL2 imprinted domain, and trans interaction between the products of reciprocally imprinted genes.[7]

Function

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In mouse models, maternal deletion of Meg3 causes skeletal muscle defects and perinatal death, indicating a role in normal tissue development.[5]

Meg3 constrains angiogenesis under normal conditions. Its loss increases expression of angiogenesis-promoting genes and microvessel formation in the brain, indicating that MEG3 normally restrains new blood vessel formation.[5] MEG3 supports normal endothelial cell function by regulating the DNA damage response, contributing to vascular integrity.[8]

MEG3 forms RNA–DNA triplex structures at GA-rich chromatin sites, acting as a molecular adaptor that guides PRC2/EZH2 to target genes such as those of the TGF-β pathway.[9]

MEG3 is involved in negative regulation of cell growth under normal conditions, indicating that healthy tissues rely on baseline MEG3 activity to keep proliferation properly restrained.[4]

Clinical significance

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Cancer

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MEG3 expression is lost or reduced,[6][10] frequently through promoter hypermethylation, in an expanding list of primary human tumors and cancer cell lines across many tissue types, making it one of the first lncRNAs identified as a tumor suppressor.[5][11]

It acts as a growth suppressor in tumour cells, and activates p53.[10][12] A conserved pseudoknot in exon 3 was shown to be essential for p53 pathway upregulation.[13]

MEG3 normally stabilizes and increases p53 protein levels and enhances transcription of p53 target genes; its loss removes this brake on proliferation and apoptosis resistance.[5] MEG3 loss de-represses RB, MYC, and PTEN regulation and the Wnt/β-catenin, PI3K/AKT, JAK/STAT, and VEGF pathways, permitting uncontrolled proliferation, epithelial–mesenchymal transition, and angiogenesis.[11][14] MEG3 normally sequesters specific microRNAs (e.g., miR-21, miR-127, miR-421); its loss releases these oncogenic miRNAs to silence tumor-suppressive targets.[15]

Low or absent MEG3 expression correlates with faster tumor growth, earlier metastasis, worse prognosis, and reduced chemosensitivity (e.g., to cisplatin, paclitaxel, oxaliplatin, and gemcitabine).[15][16][11]

Specific MEG3 polymorphisms (rs7158663, rs4081134, rs11160608) are associated with increased cancer risk, and rs10132552 with therapeutic response.[11]

MEG3 dysregulation has been implicated as a mechanism in cancers driven by exposure to carcinogenic metals.[17]

Loss of MEG3 expression is strongly associated with tumor grade in meningioma, with allelic loss and promoter hypermethylation of MEG3 increasing in prevalence in higher-grade tumors.[18]

Developmental abnormalities

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The expression profile in mouse of the co-regulated Meg3 and Dlk1 genes suggests a causative role in the pathologies found in uniparental disomy animals, characterized by defects in skeletal muscle maturation, bone formation, placenta size and organization and prenatal lethality. The sheep homolog is associated with the callipyge mutation which in heterozygous individuals affects a muscle-specific long-range control element located in the DLK1-GTL2 intergenic region and results in the callipyge muscular hypertrophy.

Alzheimer's disease

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MEG3 is thought to play a role in the development of Alzheimer's disease by triggering necroptosis.[19][20]

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000214548 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Entrez Gene: MEG3 maternally expressed 3".
  4. 1 2 3 "MEG3 maternally expressed 3 [Homo sapiens (human)]". Gene. National Center for Biotechnology Information. Retrieved 2026-08-09.
  5. 1 2 3 4 5 Zhou Y, Zhang X, Klibanski A (2012-04-02). "MEG3 noncoding RNA: a tumor suppressor". Journal of Molecular Endocrinology. 48 (3): R45–R53. doi:10.1530/JME-12-0008. PMC 3738193. PMID 22393162.
  6. 1 2 Zhang X, Rice K, Wang Y, Chen W, Zhong Y, Nakayama Y, et al. (March 2010). "Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions". Endocrinology. 151 (3): 939–947. doi:10.1210/en.2009-0657. PMC 2840681. PMID 20032057.
  7. ↑ Miyoshi N, Wagatsuma H, Wakana S, Shiroishi T, Nomura M, Aisaka K, et al. (March 2000). "Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q". Genes to Cells. 5 (3): 211–220. doi:10.1046/j.1365-2443.2000.00320.x. PMID 10759892.
  8. ↑ Shihabudeen Haider Ali MS, Cheng X, Moran M, Haemmig S, Naldrett MJ, Alvarez S, et al. (2019-02-20). "LncRNA Meg3 protects endothelial function by regulating the DNA damage response". Nucleic Acids Research. 47 (3): 1505–1522. doi:10.1093/nar/gky1190. PMC 6379667. PMID 30476192.
  9. ↑ Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, et al. (2015-07-24). "MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures". Nature Communications. 6 7743. doi:10.1038/ncomms8743. PMC 4525211. PMID 26205790.
  10. 1 2 Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, et al. (November 2003). "A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells". The Journal of Clinical Endocrinology and Metabolism. 88 (11): 5119–5126. doi:10.1210/jc.2003-030222. PMID 14602737.
  11. 1 2 3 4 Ghafouri-Fard S, Taheri M (October 2019). "Maternally expressed gene 3 (MEG3): A tumor suppressor long non coding RNA". Biomedicine & Pharmacotherapy. 118 109129. doi:10.1016/j.biopha.2019.109129. PMID 31326791.
  12. ↑ Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al. (August 2007). "Activation of p53 by MEG3 non-coding RNA". The Journal of Biological Chemistry. 282 (34): 24731–24742. doi:10.1074/jbc.M702029200. PMID 17569660.
  13. ↑ Uroda T, Anastasakou E, Rossi A, Teulon JM, Pellequer JL, Annibale P, et al. (September 2019). "Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway". Molecular Cell. 75 (5): 982–995.e9. doi:10.1016/j.molcel.2019.07.025. PMC 6739425. PMID 31444106.
  14. ↑ Zheng Q, Lin Z, Xu J, Lu Y, Meng Q, Wang C, et al. (2018-02-15). "Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN". Cell Death & Disease. 9 (3) 253. doi:10.1038/s41419-018-0305-7. PMC 5833746. PMID 29449541.
  15. 1 2 Xu J, Wang X, Zhu C, Wang K (2022-12-05). "A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers". Frontiers in Cell and Developmental Biology. 10 997633. doi:10.3389/fcell.2022.997633. PMC 9760833. PMID 36544907.
  16. ↑ Ma L, Wang F, Du C, Zhang Z, Guo H, Xie X, et al. (2018). "Long non-coding RNA MEG3 functions as a tumour suppressor and has prognostic predictive value in human pancreatic cancer". Oncology Reports. 39 (3): 1132–1140. doi:10.3892/or.2018.6178. PMID 29328401.
  17. ↑ Zhang Z, Shi S, Li J, Costa M (2023-02-07). "Long Non-Coding RNA MEG3 in Metal Carcinogenesis". Toxics. 11 (2): 157. doi:10.3390/toxics11020157. PMC 9962265. PMID 36851033.
  18. ↑ Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, et al. (2010-03-15). "Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression". Cancer Research. 70 (6): 2350–2358. doi:10.1158/0008-5472.CAN-09-3885. PMC 2987571. PMID 20179190.
  19. ↑ Balusu S, Horré K, Thrupp N, Craessaerts K, Snellinx A, Serneels L, et al. (2023). "MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease". Science. 381 (6663). New York, N.Y.: 1176–1182. Bibcode:2023Sci...381.1176B. doi:10.1126/science.abp9556. PMC 7615236. PMID 37708272.
  20. ↑ "Scientists discover how brain cells die in Alzheimer's". BBC News. 2023-09-15. Retrieved 2023-09-27.

See also

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Further reading

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