TY - JOUR
T1 - LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids
AU - Mitsuya, Kohzoh
AU - Meguro, Makiko
AU - Lee, Maxwell P.
AU - Katoh, Motonobu
AU - Schulz, Thomas C.
AU - Kugoh, Hiroyuki
AU - Yoshida, Mitsuaki A.
AU - Niikawa, Norio
AU - Feinberg, Andrew P.
AU - Oshimura, Mitsuo
N1 - Funding Information:
The authors thank A. Kashiwagi and M. Kohda for technical assistance and Drs M. Nakao, T. Tada, R. Katoh and H. Sasaki for valuable suggestions. K.M. is a Research Fellow of the Japan Society for the Promotion of Science. The Feinberg laboratory contributed the analysis of Wilms’ tumor specimens to this work. This work was supported by the Japan Science and Technology Corp., Japan (M.O.), and NIH grant CA65145 (A.P.F.).
PY - 1999
Y1 - 1999
N2 - 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 KvLQTI 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.
AB - 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 KvLQTI 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.
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U2 - 10.1093/hmg/8.7.1209
DO - 10.1093/hmg/8.7.1209
M3 - Article
C2 - 10369866
AN - SCOPUS:0032813924
SN - 0964-6906
VL - 8
SP - 1209
EP - 1217
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -