The Importance Of Gene Location

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The Importance Of Gene Location

http://www.medicalnewstoday.com/articles/97314.php

Moving an active gene from the interior of the nucleus to its

periphery can inactivate that gene report scientists from the

University of Chicago Medical Center in an article to be published

early online Feb.13, 2008, in the journal Nature.

Attachment to the inner nuclear membrane, they show, can silence

genes, preventing their transcription--a novel form of gene

regulation.

" Several years ago, we and others described the correlation between

nuclear positioning and gene activation, " said study author Harinder

Singh, Louis Block Professor of Molecular Genetics and Cell Biology

and an Investigator in the Medical Institute at the

University of Chicago.

" With that in mind, we wanted to take the next step, to design an

experiment that could test causality. Could we move a gene from the

center of the nucleus to the periphery, we asked, and then measure

the consequences of such repositioning? "

In mammalian nuclei, chromatin--a complex of DNA and associated

proteins--is organized into structural domains through interactions

with distinct nuclear compartments. In this study, the authors

developed the molecular tools to take specific genes from these

interior compartments, move them to the periphery and attach them to

the nuclear membrane--which turned those genes off.

Not only were selected " test " genes that served as markers turned off

after being attached to the inner nuclear membrane, but also

nearby " real " genes.

Singh's laboratory had become interested in studying the role of

nuclear postioning in the control of gene activity based on work

analyzing immunoglobulin heavy-chain genes. These genes are assembled

by DNA recombination and code for proteins that are a crucial part of

antibodies, produced in antibody-secreting lymphocytes or B-cells.

" In cells that don't produce antibodies, like fibroblasts or T-cells,

these antibody genes are attached to the inner nuclear membrane and

are not recombined or expressed, " said Singh.

On the other hand, antibody genes are actively transcribed and

recombined in developing B-cells, and therefore positioned in the

nuclear interior, far away from the periphery.

Five years ago, Singh and colleagues reported in Science that even in

developing B cells, antibody genes start off at the nuclear

periphery. As young cells mature and prepare to produce antibodies,

however, these genes move to the interior of the nuclei.

The exact ways in which positioning at the outer edge of the nucleus

prevents gene expression are still unclear. The likely suspects, said

Singh, are some of proteins that reside in the inner nuclear

membrane.

These proteins may be involved in blocking transcription, he said.

They accumulate at sites of attachment and come in contact with parts

of certain silenced genes. " So we think that these proteins are part

of the molecular machinery that is used for positioning genes at the

inner nuclear membrane, as well as potentially for repressing them, "

he said.

In their Nature paper, Singh's team also showed for the first time

that this transcriptional repression was dependent on breakdown and

reformation of the nuclear membrane during cell division.

The reorganizing of chromosomes occurs when cells divide. " This

suggests that cell division is used not only to transmit the genetic

information into daughter cells and create two equivalent cells, " he

said, " but it is also an opportunity for cells to reorganize their

genomes in 3D space, sequestering parts of the genome at the nuclear

periphery and rendering it inaccessible to transcription. "

Singh and colleagues are now looking for examples of striking

reorganization of the genome separated by one cell division--in which

active genes, that will not be active after the cell divides, get

pushed away from the interior to the periphery.

The lead author, Reddy, a postdoctoral fellow in the Singh

laboratory, proposes that, such compartmentalization " implies the

existence of DNA segments that encode for 'nuclear addresses' acting

like a nuclear zip code to direct or predispose genes to associate

with specific regions within the nucleus. This could be tremendously

important, " she said, " for understanding the underlying cause of some

diseases that result from mutations in genes encoding inner nuclear

membrane proteins. "