A new study reveals how transcription factors, proteins that regulate genes, work together to shape cellular identity. The research uncovers a "guided search" mechanism, where DNA and chromatin structure act as a roadmap, directing these proteins to specific genetic targets. This discovery offers new insights into how cells develop and could advance regenerative medicine.

[Hebrew University of Jerusalem]– A new study led by Prof. Yosef Buganim from the Faculty of Medicine at the Hebrew University and Dr. Abdenour Soufi from the University of Edinburgh, has uncovered a sophisticated mechanism that explains how cells determine their identity. This research sheds light on the complex interplay between proteins and DNA that governs the formation of different cell types in the body.

The study focused on transcription factors (TFs), proteins that bind to specific DNA sequences to regulate the activity of genes. These proteins are critical for determining a cell's role—for instance, whether it becomes a skin cell, a muscle cell, or a neuron. While it has long been understood that TFs recognize specific DNA sequences, this alone does not fully explain how they select the specific genes they activate to shape cellular identity.

By comparing how different combinations of TFs influence cell states, the team analyzed their behavior at unprecedented detail. Using advanced techniques, they studied the proteins’ interactions with DNA, how they affect chromatin (the structure that organizes DNA), and how they navigate the 3D landscape of the genome. Their findings revealed that TFs work together in dynamic ways, sometimes cooperating and other times competing, to target specific regions of DNA.

One striking discovery was how TFs navigate the intricate structure of chromatin. In some cases, the proteins follow directional cues provided by DNA patterns, using chromatin loops as pathways to reach their target genes. In others, they cluster at junctions where chromatin is tightly packed with DNA motifs, before spreading to activate genes necessary for a specific cell type. These pathways act as signposts, guiding the TFs to the precise genetic switches they need to flip.

This study proposes a new “guided search” model, where the arrangement of DNA and chromatin acts as a roadmap for transcription factors. This insight deepens our understanding of how cellular identity is established and maintained and may pave the way for advances in regenerative medicine and cell therapy by enabling scientists to better control how cells develop and function.

This research offers a powerful tool for unraveling the complexities of gene regulation, providing hope for tackling diseases linked to cellular dysfunction