Gene regulation has long been described as a sequence of distinct steps: first, transcription factors switch genes on or off, then other molecules step in to process the RNA and direct protein production. But a growing number of findings suggest that this division of labor may not be so clear-cut. A new study from SISSA, led by Antonello Mallamaci and published in Neural Regeneration Research, shows that a substantial portion of mammalian transcription factors can physically interact with proteins involved in downstream steps of gene expression.
The study reveals that about 20% of known transcription factors in mammals interact with proteins involved in processes such as splicing, polyadenylation, RNA transport, and the initiation of translation. These interactions, identified through systematic analysis of public datasets and supported by experimental evidence, suggest that gene regulation may often rely on more integrated mechanisms than previously thought.
The results also raise evolutionary questions. This multifunctionality could have emerged to avoid gene duplication in dosage-sensitive systems, to ensure tighter coordination in tissues such as the nervous system, or as a result of selective reuse of protein sequences capable of weak RNA binding. The three hypotheses will need experimental validation, but are already supported by available data. “Further studies will be needed to determine how widespread and functionally relevant this phenomenon is across different tissues,” says Mallamaci. “But the fact that the same protein can take on two such distinct regulatory roles already marks a significant departure from the classical model of transcription factor evolution.”
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