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.
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