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Monday, January 14, 2013

Gene position affects gene activity

Thanks to work on epigenetics, we now know that there's more to genes than just the underlying DNA sequence. In fact, according to University of California, San Diego researchers led by Menzies Chen, epigenetics may be used to tease out whether the location of a gene within the genome can affect that gene's expression.

Epigenetics involves the modification of not only DNA itself, but also of protein complexes associated with DNA. For example, the histones that wrap up DNA into chromatin can be methylated, and these modifications are correlated with changes in transcription activity. It just isn’t clear which is the cause and which the effect. In other words, do transcription levels alter histone modification patterns, or do the histones cause the changes in gene expression? If the former, the activity level of a gene shouldn't change if the gene were moved to a new site. On the other hand, if the latter possibility is true, the gene activity would depend on the local histones at its new location.

This might be extremely tricky to elucidate if it weren't for the genome deletion library of the yeast Saccharomyce scerevisiae. For nearly every gene (over 90% of them anyway), there exists a strain of yeast in which that gene is deleted. In place of each missing gene is a recorder gene. The UCSD researchers were able to use this deletion library to test how the activity of the recorder gene was influenced by its position within the genome.

Because some genes are obviously essential for life, even for a yeast, the researchers used heterozygous organisms. This means that each yeast cell had one normal gene and one gene replaced by the recorder. Thus, the scientists could determine the transcription levels of the recorder in a more or less normally functioning yeast cell.

The genomic environment (modification of histones) was not altered by the substitution of the recorder for the original gene. On the other hand, about 35% of the difference in recorder expression was due to its position within the genome. This suggests that the histones affect transcription and not the other way around. This question is far from settled yet, though, as other studies have found differing results. Even in this study, one particular type of modified histone had a different effect on the recorder gene than on the normal genes that the recorder replaced. It’s not clear why that would be.

If nothing else, this gene replacement study serves as a proof of concept for studying genome location questions.

Chen, M., Licon, K., Otsuka, R., Pillus, L., & Ideker, T. (2013). Decoupling Epigenetic and Genetic Effects through Systematic Analysis of Gene Position Cell Reports DOI: 10.1016/j.celrep.2012.12.003.