A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies.

Jingnan Sun,Hong Wang,Guanjun Wang,Andrew R Hoffman,Jiuwei Cui,Yunpeng Sun,Ji-Fan Hu,Xue Wen,Dehai Yu,Wei Li

doi:10.1093/nar/gku549

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.

Highlights

Dysregulation of the genes encoding members of the insulin-like growth factor axis, including the receptor IGF1R and the ligands IGF1 and IGF2, can contribute to the progression and metastasis of human cancers [1,2,3,4,5]
Using a novel R3C (RNA-guided Chromatin Conformation Capture) method recently developed in our lab (Supplementary Figure S1) [22], we demonstrate the presence of a novel long noncoding RNA originating from the IGF1R promoter. lncRNAs have been implicated in a number of regulatory functions in eukaryotic genomes [23,24,25], including the epigenetic regulation in cis and in trans of a cluster of genes within large chromosomal domains [26,27,28,29,30]
IGFIR is frequently overexpressed in both solid tumors and hematopoietic malignancies, participating in the regulation of cancer cell proliferation, survival, metabolism and metastasis

Summary

Introduction

Dysregulation of the genes encoding members of the insulin-like growth factor axis, including the receptor IGF1R and the ligands IGF1 and IGF2, can contribute to the progression and metastasis of human cancers [1,2,3,4,5]. LncRNAs have been implicated in a number of regulatory functions in eukaryotic genomes [23,24,25], including the epigenetic regulation in cis and in trans of a cluster of genes within large chromosomal domains [26,27,28,29,30]. In this communication, we characterize the allelic expression of IRAIN lncRNA and its role in the formation of interchromosomal interactions in normal and tumor cells

Methods

Results

Conclusion