TY - JOUR
T1 - A nonimprinted Prader-Willi Syndrome (PWS)-region gene regulates a different chromosomal domain in trans but the imprinted PWS loci do not alter genome-wide mRNA levels
AU - Stefan, Mihaela
AU - Portis, Toni
AU - Longnecker, Richard
AU - Nicholls, Robert D.
N1 - Funding Information:
We thank Brande Latney for technical assistance, Dr. Don Baldwin for assistance and training with the microarray experiments, Dr. Sue Keilbaugh for training in QRT-PCR methodology, Melissa Fazzari, Drs. Hong Ji and John Tobias for helpful discussions, and Drs. John M. Greally and Don Baldwin for comments on the manuscript. This work was supported by the National Institutes of Health (HD31491 and HD36079 to R.D.N.). R.L. is supported by Public Health Service Grants CA62234, CA73507, and CA93444 from the National Cancer Institute and DE13127 from the National Institute of Dental and Craniofacial Research. M.S. is supported by an award from the American Heart Association. T.P. is a Special Fellow of the Leukemia and Lymphoma Society of America.
PY - 2005/5
Y1 - 2005/5
N2 - Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder that results from loss of function of 10 clustered, paternally expressed genes in a 1.5-Mb region of chromosome 15q11-q13. Many of the primary PWS region genes appear to have nuclear RNA regulatory functions, suggesting that multiple genetic pathways could be secondarily affected in PWS. Using a transgenic mouse model of PWS (TgPWS) with an ∼4-Mb chromosome 7C deletion of paternal origin that models the neonatal phenotype of the human syndrome we compared by oligonucleotide microarrays expression levels of ∼12,000 genes and ESTs in TgPWS and wild-type brain. Hybridization data were processed with two distinct statistical algorithms and revealed a dramatically reduced expression of 4 imprinted genes within the deletion region in TgPWS mice, with 2 nonimprinted, codeleted genes reduced twofold. However, only 3 genes outside the deletion were significantly altered in TgPWS mouse brain, with ∼1.5-fold up-regulation of mRNA levels. Remarkably, these genes map to a single chromosome domain (18B3), and by quantitative RT-PCR we show that 8 genes in this domain are up-regulated in TgPWS brain. These 18B3 genes were up-regulated in an equivalent manner in Angelman syndrome mouse (TgAS) brain, which has the same deletion but of maternal origin. Therefore, the trans-regulation of the chromosome 18B3 domain is due to decreased expression of a nonimprinted gene within the TgPWS/AS mouse deletion in mouse chromosome 7C. Most surprisingly, since 48-60% of the genome was screened, it appears that the imprinted mouse PWS loci do not widely regulate mRNA levels of other genes and may regulate RNA structure.
AB - Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder that results from loss of function of 10 clustered, paternally expressed genes in a 1.5-Mb region of chromosome 15q11-q13. Many of the primary PWS region genes appear to have nuclear RNA regulatory functions, suggesting that multiple genetic pathways could be secondarily affected in PWS. Using a transgenic mouse model of PWS (TgPWS) with an ∼4-Mb chromosome 7C deletion of paternal origin that models the neonatal phenotype of the human syndrome we compared by oligonucleotide microarrays expression levels of ∼12,000 genes and ESTs in TgPWS and wild-type brain. Hybridization data were processed with two distinct statistical algorithms and revealed a dramatically reduced expression of 4 imprinted genes within the deletion region in TgPWS mice, with 2 nonimprinted, codeleted genes reduced twofold. However, only 3 genes outside the deletion were significantly altered in TgPWS mouse brain, with ∼1.5-fold up-regulation of mRNA levels. Remarkably, these genes map to a single chromosome domain (18B3), and by quantitative RT-PCR we show that 8 genes in this domain are up-regulated in TgPWS brain. These 18B3 genes were up-regulated in an equivalent manner in Angelman syndrome mouse (TgAS) brain, which has the same deletion but of maternal origin. Therefore, the trans-regulation of the chromosome 18B3 domain is due to decreased expression of a nonimprinted gene within the TgPWS/AS mouse deletion in mouse chromosome 7C. Most surprisingly, since 48-60% of the genome was screened, it appears that the imprinted mouse PWS loci do not widely regulate mRNA levels of other genes and may regulate RNA structure.
KW - Disease mechanisms
KW - Gene expression
KW - Microarray
KW - Quantitative mRNA transcription
KW - Transregulation
UR - http://www.scopus.com/inward/record.url?scp=16244414335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=16244414335&partnerID=8YFLogxK
U2 - 10.1016/j.ygeno.2005.02.004
DO - 10.1016/j.ygeno.2005.02.004
M3 - Article
C2 - 15820315
AN - SCOPUS:16244414335
SN - 0888-7543
VL - 85
SP - 630
EP - 640
JO - Genomics
JF - Genomics
IS - 5
ER -