Electrical charges control gene expression

In living cells, DNA doesn't lie bare; it wraps around proteins called histones and folds into chromatin, a compact structure that limits and regulates access to genes. To control which genes are expressed at any given times, cells use proteins called transcription factors (TFs) that bind DNA sites matching a specific DNA sequence.

TFs come in various forms; in humans alone, there are anywhere between 1600-2000 TFs currently known, all of which work in various combinations to exact the elegant and precise gene control that keeps us—and all other living organisms—alive and functioning.

Nonetheless, TFs face challenges. They have to locate a few short target sites within the genome, among millions of decoys that have slightly different DNA sequence. Moreover, many of the targets are buried inside tightly packed chromatin.

Some TFs, known as “pioneer factors”, stand out. They bind DNA even when chromatin stays compact and help open it up for other TFs. We now know that pioneer factors are important for early development, stem cell identity, and cell fate changes, but what makes some of them better searchers than others?

Three scientists at EPFL, Sim Sakong, Beat Fierz, and David Suter set out to answer this question by studying two closely related TFs: Sox2 and Sox17. Both recognize similar DNA sequences, but Sox2 acts as a strong pioneer factor while Sox17 does not. They found that the answer lies in small differences in electric charge outside the DNA-binding domain, which strongly shape how efficiently Sox2 and Sox17 search DNA and enter chromatin.

The study is published in Nature Communications.

The researchers combined genomics, single‑molecule imaging in living cells and controlled experiments using isolated molecules in a chemically controlled environment. This allowed the team to study TF function from a genome-scale, high-level view, down to the behavior of individual proteins.

They tracked individual Sox2 and Sox17 proteins as they moved, paused, and bound to DNA, and compared them to engineered, charge‑altered variants of each TF. This let them measure how long each TF stayed attached to DNA and how quickly it searched for gene targets.

The team also engineered variants of Sox2 and Sox17 that swapped specific regions outside the main DNA‑binding domain. These regions are flexible and loosely structured, more like moving tails than rigid parts, and they carry different electrical charges. By comparing these variants, the researchers could isolate how charge alone influenced DNA search behavior on free DNA and on chromatin.

Charge makes the difference

The study showed that the key difference was the electric charge of the two TFs. Sox2 carries a positively charged region next to its DNA‑binding domain, while Sox17 carries a more negatively charged one. This subtle difference shapes how each protein searches for DNA targets.

Specifically, Sox2 moved more slowly along the strand than Sox17, but it recognized its target sites more efficiently during this sliding process, which improved overall search efficiency. This effect was amplified inside cells, where DNA is wrapped into chromatin, which is then further wrapped into more knotted-up bodies called “nucleosomes”.

The positive charges in Sox2 increased its nonspecific interactions with nucleosomes, helping it bind compact chromatin and remain there longer, thus enhancing its pioneer-factor activity.

Further confirming this, cells expressing Sox2 showed greater local chromatin opening at its binding sites than cells expressing a modified version with reduced positive charge.

Implications: from development to disease

Gene regulation underpins the development of embryos, tissue repair, and numerous diseases. The study shows that gene control does not rely only on DNA sequences or protein shapes. Simple physical properties, such as electric charge in flexible protein regions, play a decisive role.

Understanding these principles helps explain why some TFs can unlock tightly packed genes while others cannot. In the long term, this knowledge could inform efforts to reprogram cells, improve stem cell technologies, or interpret how mutations alter gene regulation in disease.