Baylor Researchers Uncover Protein ‘Bridge’ for Gene Regulation

Research from **Baylor College of Medicine** has revealed a significant mechanism by which disordered proteins interact to control gene expression. This discovery addresses a longstanding question in molecular biology regarding how proteins lacking stable structures effectively regulate gene activity. The study, published in **Molecular Cell** on **July 21, 2025**, highlights the role of a structured protein known as **β-catenin** in facilitating these interactions.

In the cellular environment, proteins play a crucial role in determining which genes are activated and when. Interestingly, many of these regulatory proteins are predominantly disordered, lacking a fixed three-dimensional structure. This characteristic has led scientists to explore how these flexible proteins can contribute to precise gene regulation. Traditional views suggested that these disordered proteins function like oil droplets, interacting in a diffuse manner. However, the latest findings suggest a more organized approach facilitated by structured proteins.

Dr. **H. Courtney Hodges**, the senior corresponding author and an associate professor at Baylor, explained that the majority of a group of proteins known as **BAF complexes**—essential for opening DNA—are disordered. He stated, “Without a fixed shape, it has been difficult to analyze how these disordered regions interact.” The study demonstrates that disordered regions of BAF proteins utilize **β-catenin** as an adapter to establish connections with other proteins essential for gene activation.

The research team focused on **adrenocortical carcinoma (ACC)**, a severe form of adrenal cancer characterized by excessive steroid production. Understanding the molecular interactions that lead to hormonal imbalances in ACC was a primary objective for the scientists. Dr. **Yuen San Chan**, the first author and postdoctoral researcher, said, “We aimed to understand the root molecular mechanisms driving these hormone disruptions to find a better way to treat this disease.”

Through their investigation, the researchers discovered that disordered proteins in BAF directly interact with the stable structure of **β-catenin**. This interaction helps the BAF complexes locate and open genes responsible for steroid enzyme production. Notably, the researchers found that this mechanism extends beyond steroid hormone regulation. Other critical gene expression regulators, including those involved in stress responses and cancer progression, similarly depend on **β-catenin** to connect with BAF.

Dr. **Katerina Cermakova**, a co-corresponding author and assistant professor of biochemistry, emphasized the implications of their findings: “Our findings challenge the way we think about disorder in biology. Interactions between disordered molecules with structured proteins give rise to a kind of hidden organization.” This suggests that, despite their seemingly chaotic nature, these proteins possess a modular and organized method for driving gene expression.

The implications of this research extend into the realm of drug development. The proteins involved in these interactions may serve as potential targets for new therapies aimed at treating diseases like ACC. Collaboration in this groundbreaking study included institutions such as **MD Anderson Cancer Center**, the **University of Michigan**, and the **University of Colorado School of Medicine**, alongside the **Institute of Organic Chemistry and Biochemistry** in the **Czech Republic**.

In summary, the work conducted by Baylor College of Medicine provides a fresh perspective on the organization of disordered proteins in gene regulation. As researchers continue to explore these interactions, it holds promise for advancing our understanding of genetic control and developing new therapeutic strategies.