TY - JOUR
T1 - ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.
AU - Arima, Takahiro
AU - Kamikihara, Tetsuya
AU - Hayashida, Toshirou
AU - Kato, Kiyoko
AU - Inoue, Toshiaki
AU - Shirayoshi, Yasuaki
AU - Oshimura, Mitsuo
AU - Soejima, Hidenobu
AU - Mukai, Tunehiro
AU - Wake, Norio
N1 - Funding Information:
We would like to thank Dr Y. Yoshikawa, Mr Komatsu and Ms H. Hachisu for technical assistance and all members of the laboratory for their support and valuable suggestion. In particular, R. John for the comments on manuscript. This work was supported by a grant from the Ministry of Health and Welfare of Japan and by The 21st Century Program: The Research Core for Chromosome Engineering Technology. Funding to pay the Open Access publication charges for this article was provided by a grant from the Ministry of Health and Welfare of Japan.
PY - 2005
Y1 - 2005
N2 - Loss of genomic imprinting is involved in a number of developmental abnormalities and cancers. ZAC is an imprinted gene expressed from the paternal allele of chromosome 6q24 within a region known to harbor a tumor suppressor gene for several types of neoplasia. p57(KIP2) (CDKN1C) is a maternally expressed gene located on chromosome 11p15.5 which encodes a cyclin-dependent kinase inhibitor that may also act as a tumor suppressor gene. Mutations in ZAC and p57KIP2 have been implicated in transient neonatal diabetes mellitus (TNDB) and Beckwith-Wiedemann syndrome, respectively. Patients with these diseases share many characteristics. Here we show that mouse Zac1 and p57Kip2 have a strikingly similar expression pattern. ZAC, a sequence-specific DNA-binding protein, binds within the CpG island of LIT1 (KCNQ1OT1), a paternally expressed, anti-sense RNA thought to negatively regulate p57(KIP2) in cis. ZAC induces LIT1 transcription in a methylation-dependent manner. Our data suggest that ZAC may regulate p57(KIP2) through LIT1, forming part of a novel signaling pathway regulating cell growth. Mutations in ZAC may, therefore, contribute to Beckwith-Wiedemann syndrome. Furthermore, we find changes in DNA methylation at the LIT1 putative imprinting control region in two patients with TNDB.
AB - Loss of genomic imprinting is involved in a number of developmental abnormalities and cancers. ZAC is an imprinted gene expressed from the paternal allele of chromosome 6q24 within a region known to harbor a tumor suppressor gene for several types of neoplasia. p57(KIP2) (CDKN1C) is a maternally expressed gene located on chromosome 11p15.5 which encodes a cyclin-dependent kinase inhibitor that may also act as a tumor suppressor gene. Mutations in ZAC and p57KIP2 have been implicated in transient neonatal diabetes mellitus (TNDB) and Beckwith-Wiedemann syndrome, respectively. Patients with these diseases share many characteristics. Here we show that mouse Zac1 and p57Kip2 have a strikingly similar expression pattern. ZAC, a sequence-specific DNA-binding protein, binds within the CpG island of LIT1 (KCNQ1OT1), a paternally expressed, anti-sense RNA thought to negatively regulate p57(KIP2) in cis. ZAC induces LIT1 transcription in a methylation-dependent manner. Our data suggest that ZAC may regulate p57(KIP2) through LIT1, forming part of a novel signaling pathway regulating cell growth. Mutations in ZAC may, therefore, contribute to Beckwith-Wiedemann syndrome. Furthermore, we find changes in DNA methylation at the LIT1 putative imprinting control region in two patients with TNDB.
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U2 - 10.1093/nar/gki555
DO - 10.1093/nar/gki555
M3 - Article
C2 - 15888726
AN - SCOPUS:18744406710
SN - 0305-1048
VL - 33
SP - 2650
EP - 2660
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 8
ER -
