Debunking myths on genetics and DNA

Monday, September 3, 2012

Transcription factories for gene expression: the hard working units of the nucleus

You've probably heard it many times already: if you could stretch out the DNA contained in any one nucleated cell in your body, it would be 2 meters (~6 feet) long. Now imagine packing this 2-meter long molecule into a sphere whose diameter is of the order of a few micrometers, roughly one millionth smaller than a meter. Yes, it's going to be packed in there, yet those genes have to be accessible to the "workers" that come in and perform daily tasks such as gene transcription, replication, and DNA repair. Clearly, which genes are accessible and which aren't is going to play a major role in the cell's life and development.

The chromatin, the ensemble of DNA and proteins inside the nucleus, is dynamically regulated. For gene expression, active genes relocate from chromosome regions and cluster into subnuclear compartments called "transcription factories for gene expression."

As you know, transcription is one of the fundamental steps in the making of proteins: the enzyme RNA polymerase II creates a complementary strand of RNA (a precursor of mRNA) from the active gene. The mRNA is then synthesized and translated into the protein's amino acid sequence. The concept of transcription factories comes from the observation that specific regions in the nucleus are highly enriched in RNA polymerase II, and those are the regions from which new RNA transcripts emerge. A second observation is that distant loci, often on different chromosomes, can interact during regulation through long-range regulatory contacts.
"Increasing numbers of examples suggest that regulatory DNA elements also seem capable of undergoing functional contacts with genes located on other chromosomes. [...] By contrast, temporarily inactive alleles are positioned away from transcription factories, suggesting that genes migrate to these subnuclear sites in order to be transcribed. Crucially, the number of transcription factories per cell is severely limited compared to the number of expressed genes, compelling genes to share the same transcription factory [1]."

The above figure is a schematic of a transcription factory: active genes from different chromosomes are recruited from the chromatin. As transcription proceeds and new RNAs are formed, the templates are reeled through the factory bringing downstream nearby genes. Transcripts generated in a transcription factory that are in close proximity have a greater chance to undergo trans-splicing, in other words, the two transcripts are joined into one even though they originated from different RNA polymerases. The resulting joint RNA is called chimeric RNA. A few studies have observed proteins generated from chimeric RNAs.

In addition to trans-splicing, close proximity in a transcription factory increases the chances of translocation, i.e. one genomic region being moved to a different locus.
"It is puzzling that a genome conformation that increases the risk of potentially grave translocations can evolutionarily persist. We speculate that three- dimensional gene clustering of transcribed loci must elicit evolutionary advantages that outweigh the dangers of translocations."
As Schoenfelder et al. conclude,
"A major challenge will be to decipher the relation between these genome conformation changes and the numerous epigenetic alterations of the genome, allowing their integration into a comprehensive picture of the spatial and functional organization of the nucleus."

[1] Schoenfelder, Stefan, et al. (2010). The transcriptional interactome: gene expression in 3D. Current Opinion in Genetics DOI: 10.1016/j.gde.2010.02.002

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