| KCNQ1OT1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | KCNQ1OT1, KCNQ1-AS2, KCNQ10T1, KvDMR1, KvLQT1-AS, LIT1, NCRNA00012, Kncq1, KCNQ1 opposite strand/antisense transcript 1 (non-protein coding), KCNQ1 opposite strand/antisense transcript 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 604115 GeneCards: KCNQ1OT1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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KCNQ1 overlapping transcript 1, also known as KCNQ1OT1, is a long non-coding RNA gene found in the KCNQ1 locus. This locus consists of 8–10 protein-coding genes, specifically expressed from the maternal allele (including the KCNQ1 gene), and the paternally expressed non-coding RNA gene KCNQ1OT1.[3] KCNQ1OT1 and KCNQ1 are imprinted genes and are part of an imprinting control region (ICR). Mitsuya identified that KCNQ1OT1 is an antisense transcript of KCNQ1. KCNQ1OT1 is a paternally expressed allele and KCNQ1 is a maternally expressed allele.[4] KCNQ1OT1 is a nuclear, 91 kb transcript, found in close proximity to the nucleolus in certain cell types.[5][6]
It interacts with chromatin, the histone methyltransferase G9a (responsible for the mono- and dimethylation of histone 3 lysine 9, H3K9), and the Polycomb Repressive Complex 2, PRC2, (responsible for the trimethylation of H3K27).[5] It plays an important role in the transcriptional silencing of the KCNQ1 locus by regulating histone methylation.[3] An 890 bp region at the 5′ end of KCNQ1OT1 acts as a silencing domain.[7][8] This region regulates CpG methylation levels of somatically acquired differentially methylated regions (DMRs), mediates the interaction of KCNQ1OT1 with chromatin and with DNA (cytosine-5)-methyltransferase 1 (DNMT1), but does not affect the interactions of histone methyltransferases with KCNQ1OT1.[8]
The misregulation of the imprinted gene KCNQ1OT1 can lead to a variety of abnormalities. The loss of the maternal methylation of the KCNQ1OT1 allele is most commonly associated with Beckwith-Wiedemann syndrome.[9] The deletion of KCNQ1OT1 in males can result in a removal of the repressor in six cis genes.[10] Offspring from the males that had KCNQ1OT1 knocked out weighed 20–25% less than the control.[10] If the deletion occurred in females, their offspring had no growth restrictions. Furthermore, uniparental paternal disomy (UPD) of KCNQ1OT1 is strongly associated with Wilms’ tumor. In fact, three out of four patients with Beckwith-Wiedemann Syndrome and Wilms’ tumor had UPD.[11] When KCNQ1OT1 transcript is truncated, normally repressed alleles on the paternal chromosome are instead expressed.[12] As the evidence shows, the misregulation of KCNQ1OT1 can lead to disastrous physical and genetic effects.
See also
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000269821 - Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 Kanduri C (June 2011). "Kcnq1ot1: a chromatin regulatory RNA". Seminars in Cell & Developmental Biology. 22 (4): 343–350. doi:10.1016/j.semcdb.2011.02.020. PMID 21345374.
- ↑ Mitsuya K, Meguro M, Lee MP, Katoh M, Schulz TC, Kugoh H, Yoshida MA, Niikawa N, Feinberg AP, Oshimura M (July 1999). "LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids". Human Molecular Genetics. 8 (7): 1209–1217. doi:10.1093/hmg/8.7.1209. PMID 10369866.
- 1 2 Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C (October 2008). "Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation". Molecular Cell. 32 (2): 232–246. doi:10.1016/j.molcel.2008.08.022. PMID 18951091.
- ↑ Fedoriw AM, Calabrese JM, Mu W, Yee D, Magnuson T (December 2012). "Differentiation-driven nucleolar association of the mouse imprinted Kcnq1 locus". G3. 2 (12): 1521–1528. doi:10.1534/g3.112.004226. PMC 3516474. PMID 23275875.
- ↑ Mohammad F, Pandey RR, Nagano T, Chakalova L, Mondal T, Fraser P, Kanduri C (June 2008). "Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region". Molecular and Cellular Biology. 28 (11): 3713–3728. doi:10.1128/MCB.02263-07. PMC 2423283. PMID 18299392.
- 1 2 Mohammad F, Mondal T, Guseva N, Pandey GK, Kanduri C (August 2010). "Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1". Development. 137 (15): 2493–2499. doi:10.1242/dev.048181. PMID 20573698.
- ↑ Engel JR, Smallwood A, Harper A, Higgins MJ, Oshimura M, Reik W, Schofield PN, Maher ER (December 2000). "Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome". Journal of Medical Genetics. 37 (12): 921–926. doi:10.1136/jmg.37.12.921. PMC 1734494. PMID 11106355.
- 1 2 Fitzpatrick GV, Soloway PD, Higgins MJ (November 2002). "Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1". Nature Genetics. 32 (3): 426–431. doi:10.1038/ng988. PMID 12410230. S2CID 24387570.
- ↑ Henry I, Bonaiti-Pellié C, Chehensse V, Beldjord C, Schwartz C, Utermann G, Junien C (June 1991). "Uniparental paternal disomy in a genetic cancer-predisposing syndrome". Nature. 351 (6328): 665–667. Bibcode:1991Natur.351..665H. doi:10.1038/351665a0. PMID 1675767. S2CID 4365894.
- ↑ Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM (May 2006). "Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes". Genes & Development. 20 (10): 1268–1282. doi:10.1101/gad.1416906. PMC 1472902. PMID 16702402.
Further reading
- Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O (September 1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence" (PDF). Nature. 377 (6547 Suppl): 3–174. PMID 7566098.
- Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S, Oshimura M, Feinberg AP (April 1999). "Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting". Proceedings of the National Academy of Sciences of the United States of America. 96 (9): 5203–5208. Bibcode:1999PNAS...96.5203L. doi:10.1073/pnas.96.9.5203. PMC 21842. PMID 10220444.
- Mitsuya K, Meguro M, Lee MP, Katoh M, Schulz TC, Kugoh H, Yoshida MA, Niikawa N, Feinberg AP, Oshimura M (July 1999). "LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids". Human Molecular Genetics. 8 (7): 1209–1217. doi:10.1093/hmg/8.7.1209. PMID 10369866.
- Smilinich NJ, Day CD, Fitzpatrick GV, Caldwell GM, Lossie AC, Cooper PR, Smallwood AC, Joyce JA, Schofield PN, Reik W, Nicholls RD, Weksberg R, Driscoll DJ, Maher ER, Shows TB, Higgins MJ (July 1999). "A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome". Proceedings of the National Academy of Sciences of the United States of America. 96 (14): 8064–8069. Bibcode:1999PNAS...96.8064S. doi:10.1073/pnas.96.14.8064. PMC 22188. PMID 10393948.
- DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg AP (March 2002). "Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects". American Journal of Human Genetics. 70 (3): 604–611. doi:10.1086/338934. PMC 384940. PMID 11813134.
- Cerrato F, Vernucci M, Pedone PV, Chiariotti L, Sebastio G, Bruni CB, Riccio A (July 2002). "The 5′ end of the KCNQ1OT1 gene is hypomethylated in the Beckwith-Wiedemann syndrome". Human Genetics. 111 (1): 105–107. doi:10.1007/s00439-002-0751-1. PMID 12136243. S2CID 32090374.
- DeBaun MR, Niemitz EL, Feinberg AP (January 2003). "Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19". American Journal of Human Genetics. 72 (1): 156–160. doi:10.1086/346031. PMC 378620. PMID 12439823.
- Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y (May 2003). "In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene". American Journal of Human Genetics. 72 (5): 1338–1341. doi:10.1086/374824. PMC 1180288. PMID 12772698.
- Diaz-Meyer N, Day CD, Khatod K, Maher ER, Cooper W, Reik W, Junien C, Graham G, Algar E, Der Kaloustian VM, Higgins MJ (November 2003). "Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome". Journal of Medical Genetics. 40 (11): 797–801. doi:10.1136/jmg.40.11.797. PMC 1735305. PMID 14627666.
- Soejima H, Nakagawachi T, Zhao W, Higashimoto K, Urano T, Matsukura S, Kitajima Y, Takeuchi M, Nakayama M, Oshimura M, Miyazaki K, Joh K, Mukai T (May 2004). "Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer". Oncogene. 23 (25): 4380–4388. doi:10.1038/sj.onc.1207576. PMID 15007390. S2CID 29576523.
- Du M, Zhou W, Beatty LG, Weksberg R, Sadowski PD (August 2004). "The KCNQ1OT1 promoter, a key regulator of genomic imprinting in human chromosome 11p15.5". Genomics. 84 (2): 288–300. doi:10.1016/j.ygeno.2004.03.008. PMID 15233993.
- Thakur N, Tiwari VK, Thomassin H, Pandey RR, Kanduri M, Göndör A, Grange T, Ohlsson R, Kanduri C (September 2004). "An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region". Molecular and Cellular Biology. 24 (18): 7855–7862. doi:10.1128/MCB.24.18.7855-7862.2004. PMC 515059. PMID 15340049.
- Arima T, Kamikihara T, Hayashida T, Kato K, Inoue T, Shirayoshi Y, Oshimura M, Soejima H, Mukai T, Wake N (2005). "ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome". Nucleic Acids Research. 33 (8): 2650–2660. doi:10.1093/nar/gki555. PMC 1097765. PMID 15888726.
- Higashimoto K, Soejima H, Saito T, Okumura K, Mukai T (2006). "Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith-Wiedemann syndrome and cancer". Cytogenetic and Genome Research. 113 (1–4): 306–312. doi:10.1159/000090846. PMID 16575194. S2CID 19219463.
- Geuns E, Hilven P, Van Steirteghem A, Liebaers I, De Rycke M (February 2007). "Methylation analysis of KvDMR1 in human oocytes". Journal of Medical Genetics. 44 (2): 144–147. doi:10.1136/jmg.2006.044149. PMC 2598054. PMID 16950814.
- Nakano S, Murakami K, Meguro M, Soejima H, Higashimoto K, Urano T, Kugoh H, Mukai T, Ikeguchi M, Oshimura M (November 2006). "Expression profile of LIT1/KCNQ1OT1 and epigenetic status at the KvDMR1 in colorectal cancers". Cancer Science. 97 (11): 1147–1154. doi:10.1111/j.1349-7006.2006.00305.x. PMID 16965397. S2CID 3193214.
- Korostowski L, Sedlak N, Engel N (September 2012). "The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart". PLOS Genetics. 8 (9): e1002956. doi:10.1371/journal.pgen.1002956. PMC 3447949. PMID 23028363.
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