Reacción a "First mapping of the human spliceosome, the machinery that allows multiplying the variety of proteins from the same DNA"

Let's imagine that our genetic information is stored in a book, and its chapters are our genes. Genes carry the information needed to make proteins, the molecules that do the actual work in the cell. When a protein is required, a chapter has to be transcribed into a molecule that carries the instructions to make the protein. However, contrary to how we read books, following pages sequentially, cells need to remove chunks of pages before the  transcript makes sense. This process is know a splicing, and it is catalyzed by the spliceosome. Very importantly as well, a given transcript may undergo diverse splicing events, producing a molecule that will encode a different protein. This is known as alternative splicing (AS), and it is at the heart of many essential regulatory schemes. 

Transcripts with sequence errors of a single base, or in the incorrect amount, can lead to disease and death. Thus is not surprising that the spliceosome includes more than a hundred factors, and hundreds more (in humans) can regulate it. However, how all this complexity works is not clear. What is the cellular code behind AS? Can it be tweaked to our advantage (e.g. to fight disease?) This question has been addressed a number of times, and we have learn about the function of some splicing factors at genomic level, or their role in all chapters (not a small feat). What it has been missing has been a more global approach. In this context, the work of Rogalska et al. is a very significant advance in our understanding of regulated splicing.  

Rogalska et al. have integrated the data from many experiments, each one being the output of the spliceosome (known as "transcriptome") when one of its components, or one of the splicing regulators, is missing. Each transcriptome is defined by the type and frequency of removed sets of pages. Thus, if the lack of two factors lead to similar transcriptomes, these factors must be functionally related. Following this rationale, and with a real tour de force, they have been able to produce a number of maps based on the closeness between transcriptomes. These maps,or networks of related factors, offer a blueprint of the inner works of the spliceosome and how they can be regulated. Importantly, they are consistent with previous knowledge of the spliceosome, which gives strong support to important predictions that can be made.

Examples of these findings are, a role in regulation for spliceosomal factors long thought to be known, or linking specific outcomes to regulatory splicing factors (surely very relevant to pharma research). Surely more will come, as their interaction maps are applied to other questions. The group of Juan Valcárcel has shown a number of times how dedication and courage to address complex questions can lead to significant discoveries.

It is important to keep in mind that this blueprint is based on looking at transcriptomes after a particular treatment to the cells. What other blueprints will be generated by other treatments? How robust are they? The sobering reality is that we are still far from fully understanding how genomes like ours work.  Without that, we will not be able to properly fight disease. The work of Rogalska et al. Is a significant step towards this goal.

In summary, Rogalska et al. have provided a blueprint of how the cellular collection of messages  to make proteins (transcriptome) is affected by changes in the machinery that  makes it. This blueprint includes the impact of hundreds of factors, thus providing a very valuable tool to develop drugs that can restore the proper transcriptome. Further research will be needed for this, but having a blueprint of effects and their interactions will be extremely valuable.