Detection of the placental epigenetic signature of the maspin gene in maternal plasma.
The discovery of fetal DNA in the plasma of pregnant women has opened up new approaches for noninvasive prenatal diagnosis and monitoring. Up to now, the lack of a fetal DNA marker that can be universally detected in maternal plasma has limited the clinical application of this technology. We hypothesized that epigenetic differences between the placenta and maternal blood cells could be used for developing such a marker. By using bisulfite DNA sequencing, the methylation status of the maspin gene promoter in placental tissues and paired maternal blood cells from pregnant women was analyzed. The maspin gene promoter was found to be hypomethylated in placental tissues and densely methylated in maternal blood cells. Genotyping of a single nucleotide polymorphism within the unmethylated maspin sequences in maternal plasma demonstrated that these sequences were derived from the fetus. By using real-time quantitative methylation-specific PCR, unmethylated maspin sequences were detected in maternal plasma in all three trimesters of pregnancy and were cleared within 24 h after delivery. The maternal plasma concentration of unmethylated maspin sequences was elevated by a median of 5.7 times in preeclamptic pregnancies compared with nonpreeclamptic pregnancies. Hypomethylated maspin DNA is the first universal marker for fetal DNA in maternal plasma, thus allowing the measurement of fetal DNA concentrations in pregnancy-associated disorders, irrespective of fetal gender and genetic polymorphisms. Differential DNA methylation between the placenta and maternal blood cells may be exploited to develop further markers for noninvasive prenatal assessment.
Chim
Stephen S C
SS
Department of Chemical Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China.
Tong
Yu K
YK
Chiu
Rossa W K
RW
Lau
Tze K
TK
Leung
Tse N
TN
Chan
Lisa Y S
LY
Oudejans
Cees B M
CB
Ding
Chunming
C
Lo
Y M Dennis
YM
D000328:Adult; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000097:blood* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015843:Serpins / Q000097:blood* / Q000235:genetics
D005819:Genetic Markers; C085344:SERPIN-B5; D015843:Serpins; D004247:DNA