A Transcription Factor’s Critical Mechanism is Revealed

Transcription factors are proteins that interact with DNA to control the activity of other genes. In general, a single transcription factor binds to several sites in the genome as it organizes complex cellular responses, which require the activation or inhibition of several genes. FoxH1 is an important transcription factor during embryonic development, and, in adults, it is related to the development of lung cancer and other types of leukemia.

IRB Barcelona scientists led by ICREA researcher Dr. Maria J. Macias described, at the atomic level, the mechanism by which the FoxH1 factor binds to DNA. In other words, they described and produced 3D models that replicate how FoxH1 binds to specific elements in the genome to do its job.

“FoxH1 aroused the interest of our laboratory and others because it plays a very important role in embryonic development and the development of some tumors. Although its importance has been known for a long time, It was not possible to explain the binding of DNA until now,” explained Dr. Macías, head of the Structural Characterization of Macromolecular Assemblies lab at IRB Barcelona. He adds: “The structural details we discovered in this work may allow the development of specific molecules that interact with FoxH1 and that, in the future, may lead to the development of drugs to treat diseases in which this protein is play an important role in it.”

An unusual method of binding

FoxH1 belongs to a very large family of transcription factors called FOX, but it has other characteristics. What has attracted the most attention of researchers is the ability to bind DNA even when it is linked and protected by things called nucleosomes.

To attach to DNA and carry out their regulatory functions, many transcription factors require this molecule to unwind and thus express itself. Transcription factors such as FoxH1, which bind to integrated DNA are known as transcription factors.

“In addition, the DNA sequence to which FoxH1 binds is different from the sequence recognized by other transcription factors in its family, so we wanted to understand the structural features that allow FoxH1 to acquire this very specific property ,” said Dr. Eric Aragon.

“We are very pleased to have been able to resolve these structures below 1Å resolution because it allows us to describe the interactions in detail,” concluded Dr. Radoslaw Pluta, a postdoctoral researcher from the same laboratory. Doctor. Aragón and Pluta are the first authors of the study.

Future laboratory work will focus on defining the interaction between FoxH1 and nucleosomes at the atomic scale.

Reference: Pluta R, Aragon E, Prescott NA, et al. The molecular basis for DNA recognition is the maternal transcription factor FoxH1. Nat Common. 2022;13(1):7279. doi: 10.1038/s41467-022-34925-y

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