Noninvasive Prenatal Methylomic Analysis by Genomewide Bisulfite Sequencing of Maternal Plasma DNA F.M.F. Lun, R.W.K. Chiu, K. Sun, T.Y. Leung, P. Jiang,
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Noninvasive Prenatal Methylomic Analysis by Genomewide Bisulfite Sequencing of Maternal Plasma DNA
F.M.F. Lun, R.W.K. Chiu, K. Sun, T.Y. Leung, P. Jiang, K.C.A. Chan, H. Sun, and Y.M.D. Lo
Epigenetics Refers to cellular and biological mechanisms that alter
gene expression or the expressed function of DNA without changing the DNA sequence.
Examples of epigenetic mechanisms include DNA methylation, histone modifications, chromatin remodeling and noncoding RNAs.
DNA methylation Is one of the most commonly studied epigenetic
phenomenona and is mostly in the form of cytosine methylation. This refers to the addition of a methyl group to the 5' carbon of cytosine residues in CpG dinucleotides.
DNA methylation and development DNA methylation plays a role in the control of gene
expression, gene promoter function, X chromosome inactivation and genomic imprinting.
Researchers have much interest in studying the role of DNA methylation in fetal growth and development as well as patterns of aberrant methylation related to fetal or pregnancy-associated pathologies.
However, fetal or placental tissues are not readily available from viable pregnancies before term.
Circulating cell-free fetal DNA During pregnancy, DNA mostly from dying placental
cells are released into the mother’s blood. Such fetal DNA molecules are found among a major background of the mother’s DNA in maternal plasma.
The circulating fetal DNA molecules are cell-free in nature and exist as short fragments.
Cell-free fetal DNA therefore is a source of fetal genetic material that could be sampled noninvasively through the collection of a mother’s blood sample.
Describe the two different approaches used in this study to determine the fetal / placental methylation profile from maternal plasma despite the presence of the large background of maternal DNA
Noninvasive genomewide profiling of the placental methylome
Through the analysis of maternal plasma, the placental tissue methylation profile was successfully determined in a genomewide manner.
The noninvasive nature of this approach enabled one to serially monitor the changes of the placental tissue methylation profile throughout pregnancy as shown for the studied pregnancy.
Figure 1. Circos plots of methylation density per 1-Mb bin. Chromosome ideograms (outermost ring) are oriented pter-qter in a clockwise direction (centromeres are shown in red). The second outermost track shows the number of CpG sites in the corresponding 1-Mb regions up to 20,000 sites. The methylation densities of the corresponding 1-Mb regions are shown in the other tracks based on the color scheme shown in the center. From inside to outside: chorionic villus sample, fetal-specific reads in maternal plasma, shared reads in maternal plasma, combined fetal and non-fetal reads in maternal plasma, and maternal blood cells.
Genomewide Genomewide methylation methylation profile of the profile of the first trimester first trimester samplessamples
Applications The study further shows that the data enabled the
noninvasive assessment of trisomy 21, the imprinting status of genes, gestational-age dependent changes in DNA methylation of gene loci, relationship between DNA methylation and the size of plasma DNA fragments, and the noninvasive search for placental tissue specific methylation markers.
Other potential applications are also described in the Editorial commentary that accompanies the article.
Figure 3. Methylation densities and sizes of plasma DNA molecules. First trimester maternal plasma. Data for all the sequenced reads that covered at least one CpG site are represented by the blue curve. Data for reads that also contained a fetal-specific SNP allele are represented by the red curve. Data for reads that also contained a maternal-specific SNP allele are represented by the green curve.