Did You Ever Wonder . . ?

Following the protein trail

In the laboratory, chromosomal DNA fastens onto material left over when the cell nucleus is extracted with a high-salt-concentration solution. (Although this proteinaceous stuff is called the nuclear matrix, the term was long viewed with suspicion, for lack of direct evidence that any such matrix exists in the undamaged nucleus.)

In the 1990s Terumi Kohwi-Shigematsu and Yoshinori Kohwi were investigating these "matrix attachment regions" (MARs). Within MARs, the two researchers discovered shorter sequences rich in adenine and thymine bases (A and T). Chloracetaldehyde probes revealed that here, double-stranded DNA easily unzips into single strands under the strain imposed by a salty environment. They named their discovery "base unpairing regions" (BURs).

"We reasoned that if these regions were biologically important, there must be an important protein associated with them," says Kohwi-Shigematsu. With BURs as bait, they fished among millions of clones that express proteins and snagged "special AT-rich binding protein 1," SATB1.

Found in the precursors of T cells, SATB1 also occurs in other progenitor cells. Says Kohwi-Shigematsu, "It looks like it is developmental-state specific." And it's a first: a protein that forms a structure corresponding to what a real nuclear matrix should be.

 
 
In DNA sequences known as base unpairing regions (BURs), one strand consists exclusively of well-mixed A's, T's, and some C's. Here double-stranded DNA readily separates.
 

Arming the immune system

The immune system's most important cells include killer T cells, which attack disease agents directly, and helper T cells that identify targets and stimulate the body's defenses.

T stands for thymus, the gland where T cells develop from precursor thymocytes. Before maturing into distinct types, thymocytes show both of two protein markers, CD4 and CD8. At this double-positive stage thymocytes grow abundantly, but are soon winnowed into single-positive CD4 helpers or CD8 killers.

Each type has a chemical arsenal. For example, helper cells secrete interleukin 2, identifying disease agents and stimulating other T cells to multiply and attack.

Terumi Kohwi-Shigematsi and her colleagues showed that SATB1 regulates numerous genes needed for the development of mature T cells, including the interleukin-2 receptor alpha gene. Specially bred mice without SATB1 are small and thin and live only three weeks, compared to a normal two-year lifespan. In thymocytes, lack of gene regulation by SATB1 wrecks the immune system.




Did You Ever Wonder Web Site

Ernest Orlando Lawrence Berkeley National Laboratory