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Regulating the nuclear architecture of the cell

ral region of the chromosome, the chromatin structure that plays a crucial role in chromosome segregation during cell division. What other functions abundant heterochromatin may perform are still an open question.

Even epigenetics ultimately has its roots in the genes; the researchers' first step was to identify which genes affect organization of the heterochromatin, then to identify the proteins expressed by these genes, and finally to learn how they act on the chromosomal material.

Steps along the path

Several genes previously identified in Drosophila as having a role in the suppression of gene expression, known as suppressors of variegation, were named Su(vars). The gene family known as Su(var)3-9 codes for proteins that chemically modify certain histones in the nucleosomes.

Su(var)3-9 proteins attach methyl groups to the histone labeled H3 at its ninth amino acid residue, which is a lysine. In the histone code the methylation target is known as H3K9, where K stands for lysine. Methylation of chromatin causes it to condense.

Another Su(var) gene, Su(var)2-5, makes a protein called HP1 that binds methylated H3K9 and Su(var)3-9 proteins; the effect is to further close up the chromatin, silencing genes by making access to DNA more difficult.

Other genes called E(var)s act to enhance variegation in Drosophila. One way they do this is by acetylation of the H3 histone's fourth amino acid, also a lysine. The effect is to open the chromatin at that site, making the DNA accessible.

"Acetylating H3K4 and demethylating H3K9 can activate a gene; deacetylating H3K4 and methylating H3K9 can silence it," Karpen explains. "Multiply modified at various locations, these histones are a major factor in changing the functions of chromatin, independent of DNA sequence."

Karpen and Peng studied fruit flies with mutant Su(var)3-9 genes, flies that could not produce HP1 proteins or the proteins
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Source:DOE/Lawrence Berkeley National Laboratory


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