In a groundbreaking study, scientists from Karolinska Institutet discovered that water molecules are crucial in helping transcription factors, proteins that regulate gene activity, read the human genome.
Only about 1% of our genome contains genes that make proteins. These genes are similar across mammals. Most differences between humans and other animals come from how gene activity is regulated.
Proteins called transcription factors control gene activity. They bind to specific DNA sequences, usually in the 99% of the genome that doesn’t code for proteins. By binding, they can either increase or decrease the expression of nearby genes.
Understanding how transcription factors choose their binding sites has puzzled biologists for a long time. Using detailed structural analysis and advanced computational methods, the research team has discovered that water, which makes up most of the cell’s mass, assists transcription factors in binding to DNA and differentiating between similar DNA sequences.
Mapping 50,000 DNA ”knots” in human genome
The research team found that the same transcription factor can bind to two different DNA sequences by using water differently. In one case, water molecules moved freely, increasing disorder. In the other case, water molecules “froze” between the transcription factor and DNA, connecting the two.
Understanding how transcription factors and DNA interact is crucial for normal gene regulation, understanding disease changes, and developing therapies. These findings provide important insights into gene regulation mechanisms.
The study used several advanced methods to understand how transcription factors bind to DNA:
- SELEX: To find specific DNA sequences bound by transcription factors.
- X-ray Crystallography: To solve the structures of these transcription factors bound to DNA.
- Advanced Simulations: Including the Per|Mut algorithm to measure the impact of water molecule disorder at the protein-DNA interface.
Ekaterina Morgunova, corresponding author and researcher in the Jussi Taipales Group at Karolinska Institutet, said, “The goal is to decode the regulatory grammar of our genome, understanding how DNA sequences control gene expression and how mutations affect this process.”
Journal Reference:
- Morgunova E, Nagy G, Yin Y, Zhu F, Nayak SP, Xiao T, Sokolov I, Popov A, Laughton C, Grubmuller H, Taipale J. Interfacial water confers transcription factors with dinucleotide specificity. Nat Struct Mol Biol. 2025 Jan 3. DOI: 10.1038/s41594-024-01449-6
Source: Tech Explorist
