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Stanford Team Identifies New Gene Regulation Method

NEW YORK (GenomeWeb) – A Stanford University research team has used quantitative proteomics technologies to identify a new method of gene regulation. The findings, published today in the journal Molecular Cell, reveal that there is a critical functional link between ribosome heterogeneity and post-transcriptional circuitry of gene expression.

"Until recently, ribosomes have been thought to take an important but backstage role in the cell, just taking in and blindly translating the genetic code," senior author Maria Barna, assistant professor of developmental biology and of genetics at Stanford, said in a statement. "But in the past couple of years there have been some intriguing hints of a more complex scenario. Some human genetic diseases caused by mutations in ribosomal proteins affect only specific organs or tissues, for example."

The researchers began their work by establishing a ribosome affinity purification method that identified hundreds of ribosome-associated proteins, which they published earlier this month in Cell. They then used a quantitative proteomics technology called selected reaction monitoring on a Thermo Fisher Scientific TSQ Vantage triple quadrupole mass spectrometer to analyze the data, in order to precisely calculate the quantities of each of several ribosomal proteins isolated from ribosomes within mouse embryonic stem cells.

Their calculations showed that not all the ribosomal proteins were always present in the same amount. "This discovery was completely unexpected," Barna said. "We realized for the first time that, in terms of the exact stoichiometry of these proteins, there are significant differences among individual ribosomes. But what does this mean when it comes to thinking about fundamental aspects of a cell, how it functions?"

To further investigate, Barna and her team tagged the different ribosomal proteins with CRISPR/Cas9-mediated genome editing. Then they used western blot analysis to isolate RNA molecules in the act of being translated by the ribosome.

"We found that, if you compare two populations of ribosomes, they exhibit a preference for translating certain types of genes," first author Zhen Shi said in the statement.

Shi and his colleagues were also able to identify and quantify subsets of ribosomes that are heterogeneous at the level of core ribosomal proteins. One example of this preferential translation was RPL10A/uL1-containing ribosomes. When mRNAs are enriched in binding to this type of ribosome, they are shown to require RPL10A/uL1 for their efficient translation.

The combined studies establish that ribosomal proteins found in ribosomopathies, such as Diamond-Blackfan anemia, are substoichiometric. The researchers believe this may indicate that ribosomes with specialized functions could underlie the unexpected cell- and tissue-specific congenital birth defects or disease manifestation.

Barna's team hopes to answer lingering questions in future studies For example, the researchers wrote that an "important immediate question is to determine whether a selective translational landscape of specific types of ribosomes bearing or missing certain [ribosomal proteins] exists during the course of cellular differentiation and between different cell and tissue types where the degree of ribosome heterogeneity could be even more extensive.". 

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