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Research finds copying of faithful gene via Set2 pathway

The expression of genes involves two basic steps that are,

  1. Transcription
  2. Translation

The first step in gene expression involves the exact copying of a segment of DNA into a mirror image RNA. This step is carried out in the presence of the enzyme known as RNA polymerase II, or pol II. Scientists recognize that transcription does not occur that smoothly. As the pol II glides down the DNA highway, it encounters an obstacle course of DNA tightly wound around barrier proteins called histones. For the enzyme to roll along the DNA and carry out transcription, these proteins must be shoved aside.

Researchers at the Stowers Institute for Medical Research previously showed how a protein biochemically restored an inhibitory histone landscape after a round of transcription, in order to prevent the expression of potentially harmful RNA snippets. This protein is called “Set2” and is associated with pol II.

Now, the researchers have come up with a new study that is published in the online issue of Nature. Scientists used yeast mutant in Set2 to reveal a surprising mechanism used by the cells to keep gene expression going in both appropriate and inappropriate circumstances like cancer cells. They knew that synthesis of an RNA strand must start at the beginning of a gene for it to ultimately code for a full-length protein. Moreover, it was essential to prevent RNA synthesis beginning at cryptic sites within a gene. This respective study addresses how could this happen on the molecular level.

The activation and repression of gene expression

The activation or repression of the gene expression lies within two classes of chromatin remodeling factors. The activators decorate histone proteins with acetyl groups which loosen their grip on DNA. However, the repressors include Set2 which terminates gene expression by planting methyl groups. This attracts an enzyme to snip off the acetyl groups and restore chromatin to an unapproachable state, assuring that mistaken initiation of transcription does not occur at a so-called cryptic site within a gene.

Previously, it was assumed that histones remain in contact with a DNA strand while they were decorated or stripped of acetyl groups. However, scientists did not know what happened to histones on chromatin as the RNA strand elongates. They thought that some kind of exchange of histones takes place during transcription but weren’t sure whether it happens over an entire gene.

In order to investigate potential histone reshuffling, the chemical modifications of histones, in a form of the brewer’s yeast Saccharomyces cerevisiae, were assessed. The researchers engineered the yeast to track whether labeled histones moved in and out of chromatin. Furthermore, this yeast system allowed them to compare global acetylation and methylation of histones in all 6000 genes in both Set2 mutants and normal yeast.

What were the observations?

The inhibitory methylation flag, planted by Set2 in the normal cells, widened the trajectory of genes being expressed. On the other hand, the Set2 mutants didn’t show such a mark. They showed a large portion of genes with a reciprocal increase in the acetylation mark which indicated the loss of Set2’s recruitment of the acetyl sniper.

Further analysis revealed that many of those acetylated histones had been imported from outside stores. Moreover, the results say that Set2 plays a more complex role in controlling gene expression than anticipated. Cells need Set2 under normal situations to keep the cryptic transcription start sites quiet.

The group also correlated the chemical modifications to aberrant gene expression. They used microarray analysis to show that unlike normal yeast, Set2 mutants produced variously truncated cryptic RNA transcripts. These truncated strands of RNA could possibly interfere with the translation of normal RNAs into protein.

Conclusion

The study recognizes histone exchange, over a large proportion, relevant to cancer therapies in the pipeline. Acetylation and deacetylation of histone proteins are under investigation as targets of anti-cancer drugs. Thus, it is very important to know how acetylated histones are brought to a gene.

Michelle Kwan

Michelle Kwan has studied bio-medical sciences and loves to contribute her research into the field of health through her writing. Her expertise includes product reviews and health news reporting but she enjoys writing research-based news, the most. Twitter- @MichelleKwan19

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