LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids

Abstract

Mammalian imprinted genes are frequently arranged in clusters on particular chromosomes. The imprinting cluster on human chromosome 11p15 is associated with Beckwith-Wiedemann syndrome (BWS) and a variety of human cancers. To clarify the genomic organization of the imprinted cluster, an extensive screen for differentially expressed transcripts in the 11p15 region was performed using monochromosomal hybrids with a paternal or maternal human chromosome 11. Here we describe an imprinted antisense transcript identified within the KvLQT1 locus, which is associated with multiple balanced chromosomal rearrangements in BWS and an additional breakpoint in embryonal rhabdoid tumors. The transcript, called LIT1 (long QT intronic transcript 1), was expressed preferentially from the paternal allele and produced in most human tissues. Methylation analysis revealed that an intronic CpG island was specifically methylated on the silent maternal allele and that four of 13 BWS patients showed complete loss of maternal methylation at the CpG island, suggesting that antisense regulation is involved in the development of human disease. In addition, we found that eight of eight Wilms' tumors exhibited normal imprinting of LIT1 and five of five tumors displayed normal differential methylation at the intronic CpG island. This contrasts with five of six tumors showing loss of imprinting of IGF2. We conclude that the imprinted gene domain at the KvLQT1 locus is discordantly regulated in cancer from the imprinted domain at the IGF2 locus. Thus, this positional approach using human monochromosomal hybrids could contribute to the efficient identification of imprinted loci in humans.

Extensive, clustered parental imprinting of protein-coding and noncoding RNAs in developing maize endosperm

“…In mammals, there are hundreds of imprinted long noncoding RNAs, such as Air, H19, and Kcnq1ot1 (13,34,35). Most of these RNAs play important regulatory roles within their imprinted clusters (29).…”

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

“…A role for noncoding RNAs is implicated in the regulation of imprinted genes due to the preponderance of these transcribed sequences located in imprinted domains and empirical data suggesting their importance (26,27,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, the genes Delta, Drosophila homologue-like 1 (DLK1) and maternally expressed gene 3 (MEG3) in the imprinted domain on human chromosome 14 bear remarkable similarity to the IGF2/H19 domain in terms of the genomic organization and putative regulatory features (43)(44)(45).…”

p57Kip2 and Cancer: Time for a Critical Appraisal

“…1; refs. [3][4][5][6][7][8]. In particular, CDKN1C is maternally expressed, although a faint paternal allele expression is observed in most human tissues (9).…”