A Novel Antisense Long Noncoding RNA Within the IGF1R Gene Locus is Imprinted in Hematopoietic Malignancies

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2014 Aug 6

PMID 25092925

Citations 85

Authors

Jingnan Sun

Wei Li

Yunpeng Sun

Dehai Yu

Xue Wen

Hong Wang

Jiuwei Cui

Guanjun Wang

Andrew R Hoffman

Ji-Fan Hu

Affiliations

Soon will be listed here.

Abstract

Dysregulation of the insulin-like growth factor type I receptor (IGF1R) has been implicated in the progression and therapeutic resistance of malignancies. In acute myeloid leukemia (AML) cells, IGF1R is one of the most abundantly phosphorylated receptor tyrosine kinases, promoting cell growth through the PI3K/Akt signaling pathway. However, little is known regarding the molecular mechanisms underlying IGF1R gene dysregulation in cancer. We discovered a novel intragenic long noncoding RNA (lncRNA) within the IGF1R locus, named IRAIN, which is transcribed in an antisense direction from an intronic promoter. The IRAIN lncRNA was expressed exclusively from the paternal allele, with the maternal counterpart being silenced. Using both reverse transcription-associated trap and chromatin conformation capture assays, we demonstrate that this lncRNA interacts with chromatin DNA and is involved in the formation of an intrachromosomal enhancer/promoter loop. Knockdown of IRAIN lncRNA with shRNA abolishes this intrachromosomal interaction. In addition, IRAIN was downregulated both in leukemia cell lines and in blood obtained from high-risk AML patients. These data identify IRAIN as a new imprinted lncRNA that is involved in long-range DNA interactions.

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References

Sprynski A, Hose D, Caillot L, Reme T, Shaughnessy Jr J, Barlogie B . The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood. 2009; 113(19):4614-26. PMC: 2691749. DOI: 10.1182/blood-2008-07-170464. View

Morris K . The emerging role of RNA in the regulation of gene transcription in human cells. Semin Cell Dev Biol. 2011; 22(4):351-8. PMC: 3130838. DOI: 10.1016/j.semcdb.2011.02.017. View

Rowinsky E, Schwartz J, Zojwalla N, Youssoufian H, Fox F, Pultar P . Blockade of insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): a novel approach to treatment for multiple cancers. Curr Drug Targets. 2011; 12(14):2016-33. DOI: 10.2174/138945011798829401. View

Panning B, Dausman J, Jaenisch R . X chromosome inactivation is mediated by Xist RNA stabilization. Cell. 1997; 90(5):907-16. DOI: 10.1016/s0092-8674(00)80355-4. View

Kedinger C, Gniazdowski M, Mandel Jr J, Gissinger F, Chambon P . Alpha-amanitin: a specific inhibitor of one of two DNA-pendent RNA polymerase activities from calf thymus. Biochem Biophys Res Commun. 1970; 38(1):165-71. DOI: 10.1016/0006-291x(70)91099-5. View

Doepfner K, Spertini O, Arcaro A . Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia. 2007; 21(9):1921-30. DOI: 10.1038/sj.leu.2404813. View

Zhang H, Niu B, Hu J, Ge S, Wang H, Li T . Interruption of intrachromosomal looping by CCCTC binding factor decoy proteins abrogates genomic imprinting of human insulin-like growth factor II. J Cell Biol. 2011; 193(3):475-87. PMC: 3087012. DOI: 10.1083/jcb.201101021. View

Wang J, Shen L, Najafi H, Kolberg J, Matschinsky F, Urdea M . Regulation of insulin preRNA splicing by glucose. Proc Natl Acad Sci U S A. 1997; 94(9):4360-5. PMC: 20727. DOI: 10.1073/pnas.94.9.4360. View

Yao X, Hu J, Li T, Yang Y, Sun Z, Ulaner G . Epigenetic regulation of the taxol resistance-associated gene TRAG-3 in human tumors. Cancer Genet Cytogenet. 2004; 151(1):1-13. DOI: 10.1016/j.cancergencyto.2003.08.021. View

10.

Mercer T, Mattick J . Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol. 2013; 20(3):300-7. DOI: 10.1038/nsmb.2480. View

11.

Sprynski A, Hose D, Kassambara A, Vincent L, Jourdan M, Rossi J . Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation. Leukemia. 2010; 24(11):1940-50. PMC: 3141222. DOI: 10.1038/leu.2010.192. View

12.

Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G . Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leukemia. 2011; 25(5):872-4. DOI: 10.1038/leu.2011.4. View

13.

Grandage V, Gale R, Linch D, Khwaja A . PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia. 2005; 19(4):586-94. DOI: 10.1038/sj.leu.2403653. View

14.

Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L . Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica. 2009; 95(3):415-23. PMC: 2833071. DOI: 10.3324/haematol.2009.010785. View

15.

Hu J, Vu T, Hoffman A . Differential biallelic activation of three insulin-like growth factor II promoters in the mouse central nervous system. Mol Endocrinol. 1995; 9(5):628-36. DOI: 10.1210/mend.9.5.7565809. View

16.

Shearwin K, Callen B, Barry Egan J . Transcriptional interference--a crash course. Trends Genet. 2005; 21(6):339-45. PMC: 2941638. DOI: 10.1016/j.tig.2005.04.009. View

17.

Barlow D, Stoger R, Herrmann B, Saito K, Schweifer N . The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature. 1991; 349(6304):84-7. DOI: 10.1038/349084a0. View

18.

Magistri M, Faghihi M, St Laurent 3rd G, Wahlestedt C . Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet. 2012; 28(8):389-96. PMC: 3768148. DOI: 10.1016/j.tig.2012.03.013. View

19.

Stoger R, Kubicka P, Liu C, Kafri T, Razin A, Cedar H . Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell. 1993; 73(1):61-71. DOI: 10.1016/0092-8674(93)90160-r. View

20.

Tsai C, Rowntree R, Cohen D, Lee J . Higher order chromatin structure at the X-inactivation center via looping DNA. Dev Biol. 2008; 319(2):416-25. PMC: 2567126. DOI: 10.1016/j.ydbio.2008.04.010. View