BLACKSBURG, Va., July 10, 2014 – In 1957, Conrad Waddington published a landmark essay collection that explained elegantly a concept he called “the epigenetic landscape.” It described how a cell moves through the process of cellular differentiation, becoming a blood or kidney or heart cell, much like a marble rolling down a mountain. At the time, why or how the cell became differentiated and whether it could return to its former undifferentiated state, was poorly understood.
Hehuang Xie, associate professor at Virginia Bioinformatics Institute, believes that the answer may be in DNA methylation, as described in a recent paper in Genome Research.
Epigenetics has become increasingly important, as researchers have begun to understand that it plays a great role in how traits are expressed and how the developmental history of a cell is passed down. Epigenetic changes do not occur at the level of DNA sequences but instead alter chromatin conformations that direct gene expression. These changes may be present through generations and could provide clues about inheritance of cancers and other diseases.
DNA methylation, in which a methyl group is added to DNA, is one way in which the expression of genes may be altered. DNA methylation patterns are heritable, and thus may be a way of tracing how cancers begin since the methylation pattern helps cells differentiate into specific tissues. But the inheritance of methylation patterns has been up until now very hard to track across generations.
Xie is the first to study methylation patterns across the entire genome using a technique called hairpin bisulfite sequencing. Previously, the technique has only been used to look at specific sequences in a genome to establish whether methylation patterns have been passed from mother to daughter cells. Now, for the first time, Xie has been able to look at entire genomes using next-generation sequencing techniques to monitor DNA methylation inheritance.
“In this study, we integrated hairpin bisulfite sequencing data with various -omics data to scrutinize the relationships among DNA methylation inheritance, gene expression, histone modification, transcription factor binding and distribution of 5-hydroxylmethylation cytosine,” said Xie.
“We made a number of interesting observations,” Xie continued. “For instance, accurate methylation inheritance during the stem cell transition from self-renewal to commitment is highly dependent on the binding of specific trans-factors on the local sequences. In addition, the genome-wide hairpin bisulfite sequencing technique we developed provides several advantages over traditional strategies for DNA methylation studies and does not add to the cost of sequencing.
This technique is able to capture the methylation differences between two complementary DNA strands of the “changing” methylome, and thus distinguish strand-specific DNA methylation from cell-subset specific DNA methylation within a heterogeneous cell population. It also enables the recovery of the original (pre-bisulfite converted) sequences for the identification of genetic mutations and facilitates the sequence mapping process.”
The research should lead to greater understanding about certain cancers and environmental factors contributing to them, as well as other influences on the genome that are generally harder to quantify.
July 10, 2014