(Salk Institute) Although the human genome sequence faithfully lists (almost) every single DNA base of the roughly 3 billion bases that make up a human genome, it doesn’t tell biologists much about how its function is regulated. Now, researchers at the Salk Institute provide the first detailed map of the human epigenome, the layer of genetic control beyond the regulation inherent in the sequence of the genes themselves.
This is really interesting news. The researchers have devised ways to examine the methylation pattern in genomic sequences. They call it the methylome (I’m getting a little tired of adding -ome to everything but it sounds pretty cool in this case).
Epigenetics are processes that define the expression of genes while not being a part of the genetic sequence itself. Thus, simply knowing the DNA sequence does not necessarily define everything. Two people could have the same DNA sequence but epigenetic effects can result in very different expression patterns of the genes.
We know this since every cell has the same genetic sequences but have very different expression patterns, which results in so many different types of cell in our bodies.
DNA methylation has been documented before in the regulation of gene expression. But no one has ever examined this at the single base level in human genomes, which these researchers accomplished.
They did this by a nice combination of chemistry followed by molecular biology. When cytosine, one the 4 DNA bases, is reacted with sodium bisufite, it is chemically altered. But cytosine that has been methylated will not react with sodium bisulfite and remains a cytosine.
So, after reacting with sodium bisulfite, a variety of molecular biology procedures can be performed that will differentiate the chemically altered nucleotide bases from those that remain the same. This then tells the researchers which cytosines have been methylated (they still look like cytosines) and those that are not.
They were able to sequence directly the genomes of two different cell types: stem cells, which are non-differentiated types of cells, and fibroblasts, which are terminally differentiated. Their efforts covered about 94% of all the cytosines in the human genome. The chemical procedure allowed them to determine which cytosines were methylated and which were not.
Simply looking for which cytosines were similarly methylated or not in the two cell types informed them of differential epigenetic effects in the two cells. You directly examine this data because the Salk Institute has made it available. Pretty cool. Just a few years ago this data would have been pretty well inaccessible to even most scientists. Now anyone can see it. You can even download the data.
It is a fascinating paper. What they essentially found was that the types of methylation patterns were very different in the two cell types. What was seen with fibroblasts was generally what has been seen before. But stem cells have a completely different type of methylation pattern, one that was unexpected.
They went an checked another stem cell line at specific locations to see if it also had this unusual methylation pattern and it did. Of real interest was when they examined stem cell lines that had been created by altering differentiated cell lines (that is, the cell lines were made by reversing the normal differentiation process), they again saw the appearance of the unusual methylation patterns.
A possible conclusion is that stem cells, which are generally undifferentiated and can form a wide variety of other cell types, have a very unusual form of DNA methylation that is altered substantially when they become other cell types.
That will be where they next explore. How do the methylation patterns change as the cells become more differentiated?
What this also shows is that we still have along way to go before understanding how a genomic sequence actually determines what happens inside a cell. Different methylation patterns are one instance where knowing the sequence is not the whole story.
There will probably be more instances where we are surprised. There may be other ways that epigenetic factors manipulate the genome. We may not even know what some of these are yet.
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