ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.
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.
Arima
Takahiro
T
Department of Reproductive Physiology and Endocrinology, Medical Institute of Bioregulation, Kyusyu University 4546, Tsurumihara, Beppu, Oita 874-0838, Japan.
Kamikihara
Tetsuya
T
Hayashida
Toshirou
T
Kato
Kiyoko
K
Inoue
Toshiaki
T
Shirayoshi
Yasuaki
Y
Oshimura
Mitsuo
M
Soejima
Hidenobu
H
Mukai
Tunehiro
T
Wake
Norio
N
D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019175:DNA Methylation; D003920:Diabetes Mellitus / Q000235:genetics; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D025521:Tumor Suppressor Proteins
C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; C485621:KCNQ1OT1 long non-coding RNA, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; C106464:PLAGL1 protein, human; C498423:Plagl1 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins