The Adventures of Pioneer Factors

The DNA in each of our cells is identical, but not every cell expresses it in the same way. Genes are expressed in different ways at different times to make sure that human development runs smoothly. And for this to happen, we need a substance to “read” our DNA and send its information along for translation. This is what a transcription factor does.

But sometimes DNA clumps up in a way that makes it hard for transcription factors to get to it. In those cases, a type of transcription factor called a “pioneer factor” can bind to the condensed DNA and loosen it up, allowing other transcription factors to enter. Cis-regulatory elements (CREs) are regions of DNA that regulate the transcription of neighboring genes, but they are often located within these DNA bundles and need pioneer factors to make them accessible.

In a study published in Nature Genetics, a group of researchers from the Broad Institute of Harvard and MIT led by NYSCF – Robertson Investigator Alumnus Alexander Meissner, PhD, were interested in how pioneer factors behave around CREs and how they are regulated by different co-factors and each other.

The researchers focused on three different pioneer factors: FOXA2, GATA4, and OCT4. They found that FOXA2 increased its activity more in environments that naturally contained CREs than in those engineered to contain them. FOXA2 and GATA4 also showed a bit of sampling (or low-level expression) across different cell types in natural environments. OCT4, however, only activated in specific cell types, leading researchers to believe it requires additional co-factors to start sampling.

Although FOXA2 was able to get to its target most of the time, it didn’t always make the condensed DNA more accessible. This could be due to the presence of substances called “repressors” that decrease FOXA2’s activity. When FOXA2 did make DNA more accessible, the researchers think it could be doing so by recruiting in other cellular mechanisms that modify chromatin or by displacing a certain histone (linker histone H1) to loosen up the DNA.

FOXA2 can also make DNA more accessible by decreasing DNA methylation (a process that usually keeps transcription factors from binding to DNA). However, the researchers found that FOXA2 only does this when cells are in a certain phase of the cell cycle (G1) and must wait until the cells reach a later phase (after DNA replication) before they can do it again.

Finally, the study showed that in some instances, GATA4 helps stabilize FOXA2. Future research will look into what other types of co-factors are able to stabilize pioneer factors.

Taken together, these results tell us more about how pioneer factors behave and interact with each other as well as their surroundings. For further information on this study, check out the paper in Nature Genetics.