Genetic Code For Organizing DNA Within The Nucleus Discovered By Scientists

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Genetic Code For Organizing DNA Within The Nucleus Discovered By

Scientists

http://www.medicalnewstoday.com/medicalnews.php?newsid=47763

DNA - the long, thin molecule that carries our hereditary material -

is compressed around protein scaffolding in the cell nucleus into

tiny spheres called nucleosomes. The bead-like nucleosomes are strung

along the entire chromosome, which is itself folded and packaged to

fit into the nucleus. What determines how, when and where a

nucleosome will be positioned along the DNA sequence? Dr. Eran Segal

and research student Yair Field of the Computer Science and Applied

Mathematics Department at the Weizmann Institute of Science have

succeeded, together with colleagues from Northwestern University in

Chicago, in cracking the genetic code that sets the rules for where

on the DNA strand the nucleosomes will be situated. Their findings

appeared today in Nature.

The precise location of the nucleosomes along the DNA is known to

play an important role in the cell's day to day function, since

access to DNA wrapped in a nucleosome is blocked for many proteins,

including those responsible for some of life's most basic processes.

Among these barred proteins are factors that initiate DNA

replication, transcription (the transfer of genetic information from

DNA to RNA) and DNA repair. Thus, the positioning of nucleosomes

defines the segments in which these processes can and can't take

place. These limitations are considerable: Most of the DNA is

packaged into nucleosomes. A single nucleosome contains about 150

genetic bases (the " letters " that make up a genetic sequence), while

the free area between neighboring nucleosomes is only about 20 bases

long. It is in these nucleosome-free regions that processes such as

transcription can be initiated.

For many years, scientists have been unable to agree whether the

placement of nucleosomes in live cells is controlled by the genetic

sequence itself. Segal and his colleagues managed to prove that the

DNA sequence indeed encodes " zoning " information on where to place

nucleosomes. They also characterized this code and then, using the

DNA sequence alone, were able to accurately predict a large number of

nucleosome positions in yeast cells.

Segal and his colleagues accomplished this by examining around 200

different nucleosome sites on the DNA and asking whether their

sequences have something in common. Mathematical analysis revealed

similarities between the nucleosome-bound sequences and eventually

uncovered a specific " code word. " This " code word " consists of a

periodic signal that appears every 10 bases on the sequence. The

regular repetition of this signal helps the DNA segment to bend

sharply into the spherical shape required to form a nucleosome. To

identify this nucleosome positioning code, the research team used

probabilistic models to characterize the sequences bound by

nucleosomes, and they then developed a computer algorithm to predict

the encoded organization of nucleosomes along an entire chromosome.

The team's findings provided insight into another mystery that has

long been puzzling molecular biologists: How do cells direct

transcription factors to their intended sites on the DNA, as opposed

to the many similar but functionally irrelevant sites along the

genomic sequence? The short binding sites themselves do not contain

enough information for the transcription factors to discern between

them. The scientists showed that basic information on the functional

relevance of a binding site is at least partially encoded in the

nucleosome positioning code: The intended sites are found in

nucleosome-free segments, thereby allowing them to be accessed by the

various transcription factors. In contrast, spurious binding sites

with identical structures that could potentially sidetrack

transcription factors are conveniently situated in segments that form

nucleosomes, and are thus mostly inaccessible.

Since the proteins that form the core of the nucleosome are among the

most evolutionarily conserved in nature, the scientists believe the

genetic code they identified should also be conserved in many

organisms, including humans. Several diseases, such as cancer, are

typically accompanied or caused by mutations in the DNA and the way

it organizes into chromosomes. Such mutational processes may be

influenced by the relative accessibility of the DNA to various

proteins and by the organization of the DNA in the cell nucleus.

Therefore, the scientists believe that the nucleosome positioning

code they discovered may aid scientists in the future in

understanding the mechanisms underlying many diseases.