Pioneer Transcription Factors
Pioneer transcription factors sound as if they should be riding in a covered wagon blazing a trail across the Wild West. While that’s not their role, they do, however, take the lead in facilitating cellular reprogramming and responses to environmental cues. Multicellular organisms consist of functionally distinct cellular types produced by differential activation of gene expression.
Transcription factors help this process as they seek out and bind specific regulatory sequences in DNA. That may be no easy feat to accomplish as DNA is coated with and condensed into a thick fiber of chromatin. In each eukaryotic cell, ~2 meters of DNA is packaged into a nucleus of only several microns in diameter.
“We discovered pioneer transcription factors in 1996 and were surprised to find that when they first attached to chromatin, they did not immediately activate the corresponding genes at that site,” said Kenneth S. Zaret, Ph.D., professor, department of cell and developmental biology, University of Pennsylvania School of Medicine. “By contrast, the pioneer factor endows the competence for gene activity, being among the first transcription factors to engage and pry open the target sites in chromatin.”
Dr. Zaret notes that at any one time, the vast majority of potential DNA-binding sites are not occupied, suggesting that most nuclear DNA isn’t easily accessible. The question prompted is: how do pioneer factors perform their role? An example is the pioneer transcription factor FoxA, a member of the Forkhead box family of transcription factors.
“FoxA factors engage and subsequently help activate silent genes. They are expressed in the foregut endoderm of the mouse and are necessary for induction of the liver program. We looked at the genomic location of FoxA in the adult mouse liver. We found that nearly one-third of the DNA sites bound by FoxA in the adult liver occur near silent genes.”
These studies help explain the progression of cells to cancer. “We found that in sites near where FoxA bound to silent genes, there were motifs for the transcriptional repressors Rfx1 and type II nuclear hormone receptors (HHR-II). We then confirmed protein binding and subsequent repression of adjacent FoxA sites at a novel and otherwise silent enhancer element for Cdx2. Cdx2 mediates differentiation of intestinal epithelial cells and is not normally expressed in esophageal cells. Thus, Rfx1 restricts FoxA1 activity at silent genes.
“We next examined Rfx1 in human esophageal epithelium and in adenocarcinoma and determined that Rfx1 levels decline during esophageal cancer progression, which could allow FoxA to activate Cdx2 in esophageal cells. Overall this suggests that when such networks are perturbed, cancer progression may result. It also suggests that Rfx 1 expression may serve as a biomarker for esophageal cancer progression.
“These studies illustrate how evaluating the binding of pioneer factors to silent genes may reveal the basis for how cell perturbations deregulate gene expression and progress to cancer,” Dr. Zaret concluded. “Thus, understanding how silent genes can be activated provides insights not only for development but also for cellular programming and pathogenesis.”