NONHSAT039745

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Annotated Information

Name

MEG3

Characteristics

~1.6 kb in humans with a number of splice isoforms and evidence of retained introns creating longer transcripts (Miyoshi (2000), Zhang (2010)). Similar situation in mouse and sheep with ~2kb - ~10kb transcripts due to alternative splicing, alternative 5' and 3' ends and retained introns. (Schuster-Gossler (1998), Bidwell (2001), Hagan (2009)).

Imprinted: Maternally expressed from the Dlk1-Gtl2 imprinted locus (Schuster-Gossler (1998), Miyoshi (2000)).

Function

Summary: Meg3 is important for proper growth and development and is a putative tumour suppressor which functions to activate p53 and inhibit cell proliferation. Meg3 can also control gene expression at imprinted loci through recruitment of the PRC2 complex.
Function in Cancer:. Expression of the Meg3a splicing isoform was silenced in pituitary tumours and ectopic expression was found to inhibit growth in human cancer cells, leading to the proposition that Meg3 RNA acts as a growth suppressor (Zhang (2003)).

Silencing of Meg3 is associated with meningioma pathogenesis and progression while ectopic expression inhibited growth and stimulated p53 (Zhang (2010)).

Meg3 knock-out increased expression of VEGF (Vascular Endothelial Growth Factor) signaling pathway genes in the brain, suggesting the RNA has a role in the control of vascularization, and therefore may function as a tumor suppressor in part by inhibiting angiogenesis (Gordon (2010)).
Mechanism of action:. Meg3 stimulates p53 expression and can also inhibit cell proliferation/ DNA synthesis in the absence of p53 suggesting these functions are independent of each other (Zhou (2007)), Zhang (2009). Meg3 contains several predicted secondary structural elements common to all isoforms. Replacement of the motif most important in p53 activation with a different sequence that formed the same structure maintained Meg3 function showing the RNA structural motifs are critical to Meg3 function (Zhang (2010)). Meg3 binds the PRC2 chromatin modification complex in mouse embryonic stem cells. Binding appears to be mediated by the 5'1kb of the RNA (Zhao (2010)). Controls expression of Dlk1 at the Dlk1-Meg3 imprinted locus, likely by recruiting PRC2 to the Dlk1 locus in cis. Knockdown lead to increased expression of Dlk1 and Gtl2-as along with a decrease in Ezh2/PRC2 recruitment to and H3K27me3 marks at the Dlk1 promoter (Zhao (2010)).
Developmental phenotypes:. Knockout of Meg3 and the Meg3 differentially methylated region (DMR) on the maternal allele lead to post-birth lethality, while paternal knockout lead to increased pre and post-birth lethality and growth retardation. However other lncRNAs (Rian, Meg9) were also down-regulated, perhaps due to the loss of the DMR, making attribution of the phenotype to specific lncRNAs difficult (Takahashi (2009)). A potentially more specific lacZ gene trap insertion gave a parent of origin dwarfism phenotype (Schuster-Gossler (1998)). Aberrant repression of Meg3 and other maternally expressed lncRNAs from the DLK1-Dio3 imprinting cluster is present in most induced pluripotent stem cell (iPSC) lines and is responsible for the failure of iPSCs to form viable mice (Stadtfeld (2010)). NB: iPSC embryos died mid-gestation, which was more severe than a maternal Meg3 KO (Takahashi (2009)) indicating the phenotypic impact of other lncRNAs from this locus (Stadtfeld (2010)).

Expression

Expressed in a temporal and spatially regulated manner: expressed early in mouse embryos in visceral yolk sac and embryonic ectoderm. Later in paraxial mesoderm, epithelial ducts, and also in skeletal muscle, cochlea, brain and eye (Schuster-Gossler (1998), Manji (2005)).

Dynamically expressed during mouse CNS development. This includes expression during retinal development (Blackshaw (2004)) and in many developing forebrain areas including the "diencephalon, ventral telencephalon, post mitotic cell layers of the neocortex and pyramidal cell layer of the hippocampus" (McLaughlin (2006)). Also found to be up-regulated during differentiation of neuronal progenitors to GABAergic neurons in vitro (Mercer (2010)).

Expressed in adult brain (Miyoshi (2000)) but in a more restricted manner (McLaughlin (2005)).

Isoform Meg3a is detected in human normal pituitary gland, but is absent in nonfunctioning pituitary adenomas (Zhang (2003)).

Expressed in the nucleus accumbens of normal human brains and upregulated in this brain region in heroin abusers (Michelhaugh (2010)). Conversely, levels are decreased in the caudate nucleus of patients suffering from the neurodegenerative condition, Huntington's disease (Johnson (2012)).

See cited papers for a more detailed analysis of developmental and tissue specific expression.

Conservation

Mammals. Both the human and mouse gene have ten exons with the middle exons being those which are alternatively spliced in both species (Zhang (2010)).

Misc

Contains a microRNA: miRNA 770 in the last intron, (although it appears that this intron is sometimes retained) (Hagan (2009)). A number of probes for Meg3 exist in NRED due to the large number of isoforms, accession IDs given are for probes that are common to most isoforms.

Transcriptomic Nomeclature

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Regulation

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Allelic Information and Variation

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Evolution

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Labs working on this lncRNA

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References

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Basic Information

Transcript ID	NONHSAT039745
Source	NONCODE4.0
Same with	,
Classification	intergenic
Length	1855 nt
Genomic location	chr14+:101292445..101327363
Exon number	9
Exons	101292445..101292554,101295045..101295153,101295371..101296086,101297758..101297871,101298849..101298978,101300969..101301088,101302504..101302637,101311795..101311870,101327028..101327363
Genome context
Sequence	000001 AGCCCCTAGC GCAGACGGCG GAGAGCAGAG AGGGAGCGCG CCTTGGCTCG CTGGCCTTGG CGGCGGCTCC TCAGGAGAGC 000080 000081 TGGGGCGCCC ACGAGAGGAT CCCTCACCCG GGTCTCTCCT CAGGGATGAC ATCATCCGTC CACCTCCTTG TCTTCAAGGA 000160 000161 CCACCTCCTC TCCATGCTGA GCTGCTGCCA AGGGGCCTGC TGCCCATCTA CACCTCACGA GGGCACTAGG AGCACGGTTT 000240 000241 CCTGGATCCC ACCAACATAC AAAGCAGCCA CTCACTGACC CCCAGGACCA GGATGGCAAA GGATGAAGAG GACCGGAACT 000320 000321 GACCAGCCAG CTGTCCCTCT TACCTAAAGA CTTAAACCAA TGCCCTAGTG AGGGGGCATT GGGCATTAAG CCCTGACCTT 000400 000401 TGCTATGCTC ATACTTTGAC TCTATGAGTA CTTTCCTATA AGTCTTTGCT TGTGTTCACC TGCTAGCAAA CTGGAGTGTT 000480 000481 TCCCTCCCCA AGGGGGTGTC AGTCTTTGTC GACTGACTCT GTCATCACCC TTATGATGTC CTGAATGGAA GGATCCCTTT 000560 000561 GGGAAATTCT CAGGAGGGGG ACCTGGGCCA AGGGCTTGGC CAGCATCCTG CTGGCAACTC CAAGGCCCTG GGTGGGCTTC 000640 000641 TGGAATGAGC ATGCTACTGA ATCACCAAAG GCACGCCCGA CCTCTCTGAA GATCTTCCTA TCCTTTTCTG GGGGAATGGG 000720 000721 GTCGATGAGA GCAACCTCCT AGGGTTGTTG TGAGAATTAA ATGAGATAAA AGAGGCCTCA GGCAGGATCT GGCATAGAGG 000800 000801 AGGTGATCAG CAAATGTTTG TTGAAAAGGT TTGACAGGTC AGTCCCTTCC CACCCCTCTT GCTTGTCTTA CTTGTCTTAT 000880 000881 TTATTCTCCA ACAGCACTCC AGGCAGCCCT TGTCCACGGG CTCTCCTTGC ATCAGCCAAG CTTCTTGAAA GGCCTGTCTA 000960 000961 CACTTGCTGT CTTCCTTCCT CACCTCCAAT TTCCTCTTCA ACCCACTGCT TCCTGACTCG CTCTACTCCG TGGAAGCACG 001040 001041 CTCACAAAGG GCTAATCTCG GGCCTTGTCG AAGGAAGAGG CTGCAGACGT TAATGAGGTT AGCTGCTGGA TTCCAGTATT 001120 001121 CGTCGCATAA GGATCCTTCT TTGTCTGCGA AGGAAAAACA CACTGATTAT CATAATGAGT TCCTGACCTG GCCATCCCGG 001200 001201 GGTGCCCTTG ACCAGCCCCG TGTCTCCTCA GGGTGTCCCA GCACCAGCCT GGCACAGAGT GGGGCTCAGT TAGAGTATGT 001280 001281 GGGATGTTGG TTTCGCCAGG CACGTGGGCC GTGGCCCGGC TGGGTCGGCT GAAGAACTGC GGATGGAAGC TGCGGAAGAG 001360 001361 GCCCTGATGG GGCCCACCAT CCCGGACCCA AGTCTTCTTC CTGGCGGGCC TCTCGTCTCC TTCCTGGTTT GGGCGGAAGC 001440 001441 CATCACCTGG ATGCCTACGT GGGAAGGGAC CTCGAATGTG GGACCCCAGC CCCTCTCCAG CTCGAAATCC CTCCACAGCC 001520 001521 ACGGGGACAC CCTGCACCTA TTCCCACGGG ACAGGCTGGA CCCAGAGACT CTGGACCCGG GGCCTCCCCT TGAGTAGAGA 001600 001601 CCCGCCCTCT GACTGATGGA CGCCGCTGAC CTGGGGTCAG ACCCGTGGGC TGGACCCCTG CCCACCCCGC AGGAACCCTG 001680 001681 AGGCCTAGGG GAGCTGTTGA GCCTTCAGTG TCTGCATGTG GGAAGTGGGC TCCTTCACCT ACCTCACAGG GCTGTTGTGA 001760 001761 GGGGCGCTGT GATGCGGTTC CAAAGCACAG GGCTTGGCGC ACCCCACTGT GCTCTCAATA AATGTGTTTC CTGTCTTAAC 001840 001841 AAAAAAAAAA AAAAA

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