“Transcription elongation can be sufficient, but is not necessary, to advance replication timing” EMBO Reports

DNA is the master blueprint of your identity and although manipulating DNA has played a key part in history, there are still mysteries among the two major DNA activities called transcription and replication. Transcription reads and writes parts of your DNA into a workable instruction set, while DNA replication copies the entire DNA set during cell division. Replication doesn’t happen all at once—it unfolds in temporally ordered segments and this is referred to as replication timing (RT).

In this study, published in EMBO Reports, San Diego BioMed’s Gilbert Lab and their collaborators look at how these two processes are connected and venture to make sense of contradictory literature surrounding the link between transcription and RT. Historically, researchers have known that transcription and replication must be coordinated to avoid collisions and to not occur at exactly the same time. We also know that the first DNA sequences to replicate during the cell cycle are most likely to be transcribed. That led to speculation as to whether replicating early was a pre-requisite for being transcribed, or whether transcription causes DNA to replicate early. The longstanding hypothesis has been that transcription is sufficient for early RT and perhaps drives it.

Many labs over the years tried to manipulate one and see the effect on the other but there was no solid evidence that favored a direct causal relationship. It is even possible that they are linked by some other hidden mechanisms like chromatin organization (how DNA is packaged within the cell).

In this paper, researchers directly tested that idea using cells that change into different types, stems cells becoming neural cells for instance, and asked: If we turn transcription on, does DNA get copied earlier? If we turn transcription off, does DNA get copied later?

The answer was discovered to be more nuanced. This study used modern methods to show that when genes are experimentally manipulated to be turned on, especially strongly and continuously, it can shift that DNA region to replicate earlier. So, transcription can directly influence timing, but further testing proved that transcription does not always do so, and it is not strictly required to change RT. Moreover, as researchers collected more data on these activities in many cell types, they could see that there were many examples of late replicating expressed genes, early replicating silent genes, and genes that changed their timing and transcription during differentiation of one cell type to another. Even when they completely shut off transcription throughout a region, that region of DNA still switched to early copying during development.

Overall, transcription alone can be sufficient to advance replication timing rapidly and reversibly, but it is not the only thing controlling the schedule.