Just got an email with the following article. A big deal?
Scientists Say They’ve Found a Code Beyond Genetics in DNA
By NICHOLAS WADE
Researchers believe they have found a second code in DNA in addition to the genetic code.
The genetic code specifies all the proteins that a cell makes. The second code, superimposed on the first, sets the placement of the nucleosomes, miniature protein spools around which the DNA is looped. The spools both protect and control access to the DNA itself.
The discovery, if confirmed, could open new insights into the higher order control of the genes, like the critical but still mysterious process by which each type of human cell is allowed to activate the genes it needs but cannot access the genes used by other types of cell.
The new code is described in the current issue of Nature by Eran Segal of the Weizmann Institute in Israel and Jonathan Widom of Northwestern University in Illinois and their colleagues.
There are about 30 million nucleosomes in each human cell. So many are needed because the DNA strand wraps around each one only 1.65 times, in a twist containing 147 of its units, and the DNA molecule in a single chromosome can be up to 225 million units in length.
Biologists have suspected for years that some positions on the DNA, notably those where it bends most easily, might be more favorable for nucleosomes than others, but no overall pattern was apparent. Drs. Segal and Widom analyzed the sequence at some 200 sites in the yeast genome where nucleosomes are known to bind, and discovered that there is indeed a hidden pattern.
Knowing the pattern, they were able to predict the placement of about 50 percent of the nucleosomes in other organisms.
The pattern is a combination of sequences that makes it easier for the DNA to bend itself and wrap tightly around a nucleosome. But the pattern requires only some of the sequences to be present in each nucleosome binding site, so it is not obvious. The looseness of its requirements is presumably the reason it does not conflict with the genetic code, which also has a little bit of redundancy or wiggle room built into it.
Having the sequence of units in DNA determine the placement of nucleosomes would explain a puzzling feature of transcription factors, the proteins that activate genes. The transcription factors recognize short sequences of DNA, about six to eight units in length, which lie just in front of the gene to be transcribed.
But these short sequences occur so often in the DNA that the transcription factors, it seemed, must often bind to the wrong ones. Dr. Segal, a computational biologist, believes that the wrong sites are in fact inaccessible because they lie in the part of the DNA wrapped around a nucleosome. The transcription factors can only see sites in the naked DNA that lies between two nucleosomes.
The nucleosomes frequently move around, letting the DNA float free when a gene has to be transcribed. Given this constant flux, Dr. Segal said he was surprised they could predict as many as half of the preferred nucleosome positions. But having broken the code, “We think that for the first time we have a real quantitative handle” on exploring how the nucleosomes and other proteins interact to control the DNA, he said.
The other 50 percent of the positions may be determined by competition between the nucleosomes and other proteins, Dr. Segal suggested.
Several experts said the new result was plausible because it generalized the longstanding idea that DNA is more bendable at certain sequences, which should therefore favor nucleosome positioning.
“I think it’s really interesting,” said Bradley Bernstein, a biologist at Massachusetts General Hospital.
Jerry Workman of the Stowers Institute in Kansas City said the detection of the nucleosome code was “a profound insight if true,” because it would explain many aspects of how the DNA is controlled.
The nucleosome is made up of proteins known as histones, which are among the most highly conserved in evolution, meaning that they change very little from one species to another. A histone of peas and cows differs in just 2 of its 102 amino acid units. The conservation is usually attributed to the precise fit required between the histones and the DNA wound around them. But another reason, Dr. Segal suggested, could be that any change would interfere with the nucleosomes’ ability to find their assigned positions on the DNA.
In the genetic code, sets of three DNA units specify various kinds of amino acid, the units of proteins. A curious feature of the code is that it is redundant, meaning that a given amino acid can be defined by any of several different triplets. Biologists have long speculated that the redundancy may have been designed so as to coexist with some other kind of code, and this, Dr. Segal said, could be the nucleosome code.
It is simultaneously a big deal and not a big deal. The existence of this ‘code’ has been assumed for a long time. Someone finally got clever enough to figure out a portion of it and then demonstrated that portion has some predictive accuracy. Will it fundamentally change the way most biologists do their work? No. Especially since the predictive accuracy was ‘only’ 50%. I mean on one hand that’s huge and on the other hand it means we don’t really get the full picture.
I could tell you it will revolutionize chromosome engineering or genomic medicine. But it might not. It probably explains a portion of irreproducbile results in these fields. Understanding various levels of control in a system definitely helps if you want to design something to work within that system, but is this level of control important? Under what circumstances does it over-ride other controls? This result opens up more questions than answers and (partially) addresses a long standing conundrum. I think that’s why it was published in Nature.
There’s a pretty strong chance that major portions of standard textbooks like Molecular Biology of the Cell will have to be rewritten. E.g., in the “old” paradigm the genetic code is purely digital (GCAT), and its expression is regulated by DNA-binding motifs that also can be described digitally. In the hypothesized “new” paradigm, there is an co-existing “analog” genetic code, which is present only in eukaryotes, that regulates gene expression dynamically, via nucleosome winding and unwinding. It is far from clear how to describe this co-existing code bioinformatically, or investigate it experimentally. But like “dark matter”, it clears up so many mysteries of eukaryotic genomics (why so few human genes? why so much “junk” DNA?) that people are pretty much thinking it has got to be true.
I’m with Jon on this one. It’s a big deal in the sense that it points out some interesting questions about how we can improve on their technique to get a more firm grasp on how to use these things to do specific genomic manipulations – that is, it’s a big step forward methodologically. But, it doesn’t seem like a big step forward for the theory of how DNA operates. Now, if they could show that DNA also encodes the dates of major historical events and the names of major historical figures, that might be something…
Either that intelligent designer was even busier than was thought with a crossword puzzle to fill out instead of just simple sentences, or the whole thing could evolve together without having to know which possibilities work in each direction. Either the whole thing works, or it doesn’t. If I were God I’d pick the latter. Why mess with details?
Yeah, I’m with Jon on this one. This sentence here
“like the critical but still mysterious process by which each type of human cell is allowed to activate the genes it needs but cannot access the genes used by other types of cell.”
is a little misleading because it’s not as though this discovery is the first to shed light on this. A lot is known already (though again, a lot isn’t know) about how some genes are accessible to transcription machinery but others are not. In fact it doesn’t seem to me there’s any reason this “code” they discovered is more important than the other codes already known – modifications of histones, one of the components of nucleosomes, which can be deacetylated or methylated; and modification of cytosine bases in DNA by methylation.
I talked to the press people in our biomedical research institute here, and a lot of what is made into a big science story is completely random. The people here are starving for a story about which they can write a press release, and the ones who work in our press office do not have a science background. So if they ask a scientist to explain why their work is important, then they have no background with which to judge the merits of that explanation.
A shitty paper from my lab made national news this way. The importance of the work and the specific claims made were greatly exaggerated. It’s kind of distressing. It made me stop being interested in science writing.