Providence, RI, USA. To match the two X chromosomes possessed by females, males must increase gene expression on their single X by opening the DNA helix with the male-specific lethal (MSL) protein complex.

Standard sexual dimorphism is defined by the fact that females have two X chromosomes in their genomes while males have both an X and a Y. However, this is a life-threatening genetic imbalance. Cells in mammals cells work to upregulate (emphasize) the lone X- chromosome in males and downregulate (de-emphasize) the extra X-chromosome in females. MSL gives enzymes on the X-chromosome an extra boost to increase gene expression.

The research team had a head start on understanding this process. Scientists already suspected that X-chromosome upregulation had a lot to do with the MSL protein complex that binds to the X-chromosome. The MSL is male-specific lethal because the mutant form would prove deadly. What scientists didn't know was how it worked.



RNA polymerase II (also RNAP II / Pol II) is an enzyme found in eukaryotic cells.

It catalyzes the process of creating a complementary RNA copy of a DNA sequence ( transcription) to synthesize mRNA (and most snRNA / microRNA) precursors.

For RNAP II, the initiation of transcription requires a wide range of factors that bind it to its promoters. Certain genes (estrogen response elements) can be can be expressed when activated estrogen receptors bind to them.

Estrogen increases polymerase activity in brain regions, increasing gene expression. ERa and ERß receptors, widely expressed in peripheral tissues (e.g. female genitalia) and in the central nervous system, mediate estrogen actions.

The effects of the X chromosome on brain activity are enhanced, particularly for those subjects that contain high affinity estrogen receptors.It is difficult to double the levels of expression of a wide variety of genes on one specific chromosome. However, it turns out that MSL increases gene expression on the X chromosome by openng the DNA double helix more frequently. In the language of X-chromosome upregulators (aka males), it is a specialized regulator targeted for the X-chromosome.

Erica Larschan is Assistant Professor of Biology at Brown University. She wanted to know how males so freely express the genes on their X-chromosomes when she was a postdoctoral scholar in the lab of Mitzi Kuroda at the Harvard Medical School and Brigham and Women's Hospital.

To figure out the process process now described in the journal Nature, she performed experiments using the fruitfly model, in collaboration with Eric Bishop, a graduate student at Harvard and Boston University.

It turns out that the RNA polymerase II enzyme converts DNA instructions into RNA code to express genes. Larschan and her colleagues discovered the male-specific specialization by using global run-on sequencing to measure how much of the enzyme was active in the X chromosome.

They found that to a point all chromosomes have the same amount of the enzyme. After that — farther along each gene — the X chromosome has noticeably more than other chromosomes. In other words, something allows more RNA polymerase II to move farther along the X chromosome genes, past the point where those enzymes diminish on other chromosomes.

The team showed that it was MSL by interfering with the MSL complex. By doing that, no greater amount of RNA polymerase persisted along the X-chromosome genes than along any other genes in the genome. Without MSL, the enzyme had lost its ability to push farther.

The finding that the regulation of gene expression occurs farther along genes on the X-chromosome is new, as is the discovery that MSL is promoting it, Larschan said.

"People had thought for a long time that most of the regulation was happening at the beginning of a gene, so this is a new step that people are just starting to think about, which is regulating the entry of polymerase into the rest of the gene," she said. "MSL is what's promoting this entry into the gene bodies."

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<style type="text/css"><!--.quote {width:400px; padding: 6px; border: solid 1px #456B8F; font: 11px helvetica, verdana, sans-serif; color: #222222; background-color: #ffffff}.quote a {font: 13px arial, serif; color: #003399; text-decoration: underline}.quote a:hover {color: #FF9900; }//--></style><div style="float:left;padding:5px;"><img src="../images/stories/HumanMaleSexChromosomes.jpg" width="125" alt=""/></div><div class="quote"><a href="../genetics---genome/29079-amplifying-single-x-chromosome-gene-expression" target="_blank">Amplifying Single X Chromosome Gene Expression</a><br/>Friday, 04 March 2011<div align="right" style="width:400px"><p style="text-align:right;"><a href="/" target="_blank">TS-Si.org</a></p></div></div>

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