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HGNC Approved Gene Symbol: MALAT1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,497,738-65,506,516 (from NCBI)
MALAT1 is a long noncoding RNA (lncRNA) involved in the regulation of CD8 (see 186910)-positive T-cell differentiation by mediating epigenetic repression (Kanbar et al., 2022).
The Alpha gene was identified by James et al. (1994) and by Guru et al. (1997). It is unusual in that it is very AT-rich, transcribed in an intronless fashion, and contains no ORF of significant length.
By subtractive hybridization to identify genes upregulated in aggressive nonsmall cell lung cancer, followed by 5-prime and 3-prime RACE, Ji et al. (2003) cloned 2 splice variants of MALAT1. The transcripts have putative open reading frames for peptides of about 50 amino acids, but no translation start sites have Kozak sequences. No MALAT1 protein was synthesized in an in vitro translation system. Northern blot analysis detected a MALAT1 transcript in human lung carcinoma cell lines. Real-time RT-PCR detected variable MALAT1 expression in normal tissues, with highest expression in pancreas and lung. MALAT1 homologs in several mammalian EST databases showed a high degree of sequence conservation.
Using expression arrays to identify polyadenylated RNAs displaying nuclear enrichment in human cell lines, Hutchinson et al. (2007) identified XIST (314670), NEAT1 (612769), and MALAT1, which they called NEAT2. Like NEAT1, NEAT2 is a large, infrequently spliced noncoding RNA, but it shares no sequence identity with NEAT1. Northern blot analysis detected broad expression of a NEAT2 transcript of over 6 kb, with highest expression in ovary, prostate, and colon. Hutchinson et al. (2007) also cloned mouse Neat2, and Northern blot analysis detected a broadly expressed transcript of about 7 kb in mouse tissues. Neat2 orthologs were conserved within multiple mammalian species, but not in nonmammalian species. RNA FISH analysis confirmed nuclear enrichment of NEAT1 and NEAT2 in human and mouse cell lines. Both transcripts localized with SC35 (SFRS2; 600813) at nuclear speckles, although NEAT2 was more centrally located and NEAT1 more peripherally located.
Wilusz et al. (2008) identified mascRNA, a highly conserved 61-nucleotide RNA that originates from the 3-prime end of the human MALAT1 transcript. The mascRNA transcript was predicted to fold into a tRNA-like cloverleaf. It terminates in a CCA motif, which is not encoded in the genome and is a hallmark of the 3-prime ends of tRNAs and similar structures. However, the predicted anticodon loop of mascRNA is poorly conserved, and mascRNA was not aminoacylated in HeLa cells. Like the mature 7-kb MALAT1 transcript, Northern blot analysis detected mascRNA expression in all human tissues and cell lines examined. Northern blot analysis of fractionated mouse cells showed that Malat1 localized to the nucleus, whereas mascRNA localized to the cytoplasm in mouse cells and HeLa cells.
Ji et al. (2003) found that MALAT1 was one of several genes whose expression was increased in nonsmall cell lung cancers prior to metastasizing. MALAT1 expression was associated with cancers in a stage- and histology-specific manner. Ji et al. (2003) suggested that MALAT1 expression may be a prognostic parameter for patient survival in stage I nonsmall cell lung cancer.
Wilusz et al. (2008) found that RNase P (see 606116) cleaved the nascent MALAT1 transcript downstream of a genomically encoded poly(A)-rich tract to simultaneously generate the poly(A) 3-prime end of the mature MALAT1 transcript and the 5-prime end of mascRNA. RNase Z (see ELAC2; 605367) processed the 3-prime end of mascRNA, followed by the addition of the CCA motif. Wilusz et al. (2008) also found that the nuclear MALAT1 transcript was stabilized by U-rich motifs, whereas cytoplasmic mascRNA had a relatively short half-life.
Using a random, mutagenesis-coupled, high-throughput method termed 'RNA elements for subcellular localization by sequencing' (mutREL-seq) in mouse and human cells, Yin et al. (2020) identified an RNA motif that recognized U1 snRNP (see 180680) and was essential for localization of reporter RNAs to chromatin. Across the genome, chromatin-bound lncRNAs were enriched with 5-prime splice sites and depleted of 3-prime splice sites and exhibited high levels of U1 snRNA binding compared with cytoplasm-localized mRNAs. Acute depletion of U1 snRNA or of the U1 snRNP component SNRNP70 (180740) markedly reduced chromatin association of hundreds of lncRNAs and unstable transcripts without altering the overall transcription rate in cells. Rapid degradation of SNRNP70 reduced localization of both nascent and polyadenylated lncRNA transcripts to chromatin and disrupted nuclear and genomewide localization of the lncRNA Malat1. Moreover, U1 snRNP interacted with transcriptionally engaged RNA polymerase II (see 180660). The authors concluded that U1 snRNP acts widely to tether and mobilize lncRNAs to chromatin in a transcription-dependent manner.
Using a knockdown screen, Kanbar et al. (2022) identified Malat1 as a critical regulator of mouse Cd8-positive T-cell differentiation. Furthermore, Malat1 regulated of Cd8-positive terminal effector memory (t-TEM) cell differentiation and played a role in the generation of secondary memory T cells. Single-cell RNA-sequencing analysis showed that Malat1 depletion upregulated factors associated with memory cell differentiation, suggesting that Malat1 acts specifically in cells destined to become terminal effectors and reduces expression of genes that promote memory formation. Analysis of global RNA interactions with DNA by deep sequencing revealed that Malat1 associated with a cluster of trans-interacting lncRNAs that had RNA interactions preferentially at promoters and gene bodies. Chromatin immunoprecipitation sequencing suggested that Malat1 plays a role in repressing genes associated with memory cell differentiation. Further analysis showed that Malat1 interacted with Ezh2 (601573) to maintain deposition of the epigenetic repressive mark H3K27me3 on genes associated with memory cell differentiation.
The Alpha gene maps near the multiple endocrine neoplasia type-1 locus (MEN1; 131100) on chromosome 11q13, a region implicated in chromosomal abnormalities of various tumors (James et al., 1994; Guru et al., 1997; van Asseldonk et al., 2000).
Hutchinson et al. (2007) determined that the MALAT1 and NCRNA00084 genes are less than 70 kb apart on chromosome 11q13.1. They mapped the mouse Malat1 gene to a region of chromosome 19A that shares homology of synteny with human chromosome 11q13.1.
Davis et al. (2003) cloned an Alpha/TFEB (600744) fusion gene in renal tumors harboring a t(6;11)(p21.1;q13) translocation. They found that the Alpha gene was rearranged with the first intron of TFEB, just upstream of TFEB's initiation ATG, preserving the entire TFEB coding sequence.
Kuiper et al. (2003) collected 3 cases of renal cell carcinoma (RCC; 605074) from patients 14 to 42 years of age, wherein a t(6;11)(p21;q13) translocation was the sole cytogenetic abnormality. Molecular analysis revealed fusion of the TFEB gene on chromosome 6 to the Alpha gene on chromosome 11. The Alpha/TFEB fusion gene linked all coding exons of the TFEB gene to 5-prime upstream regulatory sequences of the Alpha gene. Alpha/TFEB mRNA levels were significantly upregulated in primary tumor cells as compared with wildtype TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels. The TFEB protein encoded by the Alpha/TFEB fusion gene was efficiently targeted to the nucleus. Kuiper et al. (2003) speculated that this resulted in severely unbalanced nuclear ratios of MITF (156845)/TFE subfamily members and that this imbalance may lead to changes in the expression of downstream target genes, ultimately resulting in the development of RCC.
Davis, I. J., Hsi, B.-L., Arroyo, J. D., Vargas, S. O., Yeh, Y. A., Motyckova, G., Valencia, P., Perez-Atayde, A. R., Argani, P., Ladanyi, M., Fletcher, J. A., Fisher, D. E. Cloning of an alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc. Nat. Acad. Sci. 100: 6051-6056, 2003. [PubMed: 12719541] [Full Text: https://doi.org/10.1073/pnas.0931430100]
Guru, S. C., Agarwal, S. K., Manickam, P., Olufemi, S.-E., Crabtree, J. S., Weisemann, J. M., Kester, M. B., Kim, Y. S., Wang, Y., Emmert-Buck, M. R., Liotta, L. A., Spiegel, A. M., Boguski, M. S., Roe, B. A., Collins, F. S., Marx, S. J., Burns, L., Chandrasekharappa, S. C. A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus. Genome Res. 7: 725-735, 1997. [PubMed: 9253601] [Full Text: https://doi.org/10.1101/gr.7.7.725]
Hutchinson, J. N., Ensminger, A. W., Clemson, C. M., Lynch, C. R., Lawrence, J. B., Chess, A. A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genomics 8: 39, 2007. Note: Electronic Article. [PubMed: 17270048] [Full Text: https://doi.org/10.1186/1471-2164-8-39]
James, M. R., Richard, C. W., III, Schott, J.-J., Yousry, C., Clark, K., Bell, J., Terwilliger, J. D., Hazan, J., Dubay, C., Vignal, A., Agrapart, M., Imai, T., Nakamura, Y., Polymeropoulos, M., Weissenbach, J., Cox, D. R., Lathrop, G. M. A radiation hybrid map of 506 STS markers spanning human chromosome 11. Nature Genet. 8: 70-76, 1994. [PubMed: 7987395] [Full Text: https://doi.org/10.1038/ng0994-70]
Ji, P., Diederichs, S., Wang, W., Boing, S., Metzger, R., Schneider, P. M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., Thomas, M., Berdel, W. E., Serve, H., Muller-Tidow, C. MALAT-1, a novel noncoding RNA, and thymosin beta-4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22: 8031-8041, 2003. [PubMed: 12970751] [Full Text: https://doi.org/10.1038/sj.onc.1206928]
Kanbar, J. N., Ma, S., Kim, E. S., Kurd, N. S., Tsai, M. S., Tysl, T., Widjaja, C. E., Limary, A. E., Yee, B., He, Z., Hao, Y., Fu, X. D., Yeo, G. W., Huang, W. J., Chang, J. T. The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression. J. Exp. Med. 219: e20211756, 2022. [PubMed: 35593887] [Full Text: https://doi.org/10.1084/jem.20211756]
Kuiper, R. P., Schepens, M., Thijssen, J., van Asseldonk, M., van den Berg, E., Bridge, J., Schuuring, E., Schoenmakers, E. F. P. M., van Kessel, A. G. Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Hum. Molec. Genet. 12: 1661-1669, 2003. [PubMed: 12837690] [Full Text: https://doi.org/10.1093/hmg/ddg178]
van Asseldonk, M., Schepens, M., de Bruijn, D., Janssen, B., Merkx, G., Geurts van Kessel, A. Construction of a 350-kb sequence-ready 11q13 cosmid contig encompassing the markers D11S4933 and D11S546: mapping of 11 genes and 3 tumor-associated translocation breakpoints. Genomics 66: 35-42, 2000. [PubMed: 10843802] [Full Text: https://doi.org/10.1006/geno.2000.6194]
Wilusz, J. E., Freier, S. M., Spector, D. L. 3-prime end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135: 919-932, 2008. [PubMed: 19041754] [Full Text: https://doi.org/10.1016/j.cell.2008.10.012]
Yin, Y., Lu, J. Y., Zhang, X., Shao, W., Xu, Y., Li, P., Hong, Y., Cui, L., Shan, G., Tian, B., Zhang, Q. C., Shen, X. U1 snRNP regulates chromatin retention of noncoding RNAs. Nature 580: 147-150, 2020. [PubMed: 32238924] [Full Text: https://doi.org/10.1038/s41586-020-2105-3]