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Unraveling the Role of Pioneer Factors in Childhood Cancer

Unraveling the Role of Pioneer Factors in Childhood Cancer 150 150 Abbie Miller

New study implicates PAX3-FOXO1, an oncogenic driver of rhabdomyosarcoma, as a chimeric pioneer factor.

Transcription factors are proteins that read the DNA sequences and can direct the transcription of that sequence into mRNA for translation into a protein. Transcription can become deregulated in cancer.

Normally, transcription factors read sequences of DNA that are described as “open.” That is, they are not tightly coiled around a nucleosome.

Pioneer factors are a subset of transcription factors that can bind to “inaccessible” chromatin – and they have the capacity to bind to DNA, even when it is wrapped in a nucleosome.

Benjamin Stanton, PhD

Benjamin Stanton, PhD

“Pioneer factors live up to their name in that they can interact with regions of the DNA we normally think of as inaccessible or repressed, without spending cellular energy in the form of ATP,” says Benjamin Stanton, PhD, a principal investigator in the Center for Childhood Cancer and Blood Diseases in the Abigail Wexner Research Institute at Nationwide Children’s. “Our recent investigation is guided by the established features of bonified pioneer factors binding to compact/inaccessible chromatin and intrinsic nucleosomal motif recognition and occupancy.”

“This investigation was a team effort, and a very exciting experience,” he adds.

The team’s investigation is the subject of a recent paper published in iScience. The study shows that the oncogenic transcription factor PAX3-FOXO1 is present and acting as a pioneer factor in the context of the rare childhood cancer rhabdomyosarcoma.

The researchers demonstrated that PAX3-FOXO1 is present in not only the accessible regions in the nucleus but also in inaccessible regions, where repressive factors localize. PAX3-FOXO1 can induce local changes in nucleosome density, and restructures the chromatin in cells on a timescale of hours.

“We have been able to show that PAX3-FOXO1 recognizes chromatin as a pioneer factor, but we are still working to understand the transcriptional and chromatin structural implications,” says Dr. Stanton, who is also an assistant professor at The Ohio State University College of Medicine.

Similar to how understanding transcription factor driven tumors shifted paradigms in the cancer research community, an understanding of how pioneer factors influence cancer development could dramatically change how we understand the lineages of origin and molecular etiology of cancer.

“I think that understanding how pioneer factors work in the context of cancers – how they influence the changes in the cells and potentially result in the creation of tumor cells – will be applicable to other cancers driven by fusion oncoproteins. Pioneer factors might be able to reorganize inaccessible chromatin regardless of the type of cell in which the cancer started,” Dr. Stanton says.

 

Reference:

Sunkel BD, Wang M, LaHaye S, Kelly BJ, Fitch JR, Barr, FG, Stanton BZ. Evidence of pioneer factor activity of an oncogenic transcription factor. iScience. 20 Aug 2021;24:102867.

About the author

Abbie (Roth) Miller, MWC, is a passionate communicator of science. As the manager, medical and science content, at Nationwide Children’s Hospital, she shares stories about innovative research and discovery with audiences ranging from parents to preeminent researchers and leaders. Before coming to Nationwide Children’s, Abbie used her communication skills to engage audiences with a wide variety of science topics. She is a Medical Writer Certified®, credentialed by the American Medical Writers Association.

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