A new discovery of a key mechanism by which skin begins to develop in embryos could improve skin grafts.

Developmental biologists are still working to understand the process by which embryonic progenitors coordinate cell fate specification and establish transcriptional and signaling competence. In a new study, researchers show that transcription factor DeltaNp63 profoundly alters the transcriptome and remodels thousands and thousands of open chromatin regions of Krt8+ progenitors during epidermal fate specification.

The discovery by researchers from University of Colorado Boulder sheds light on the genetic roots of birth defects, such as cleft palate. The discovery may also help scientists develop more functional skin grafts for burn victims.

"This study maps how skin development starts, from the earliest stages," said Rui Yi, a senior author of the paper, in a press release.

Surgeons perform thousands of skin grafts each year to repair burns, wounds or birth defects. Stem cell therapy using the patient’s own skin cells to grow new skin and other advancements have improved skin transplants. While replacement skin works well to protect the body, it often lacks hair follicles, nerve endings, sweat glands or other important features.

"Skin is an incredibly complex system and the regeneration we are doing now is not even close to duplicating it," said Yi, an associate professor of molecular, cellular and developmental biology. "The overarching goal is to someday be able to regenerate fully functional skin, and to do that, we have to know, fundamentally, what happens at the beginning."

New study unveils molecular origin of epidermal cells of the skin

Using advanced DNA sequencing techniques and genomic tools, the research team observed the actions of embryonic progenitor cells of mice during the formation of skin.

The research team focused on the transcription factor that can read genetic information from the p63 genome, which is found primarily in skin cells and plays a critical role in the formation of skin.

Previous mouse studies show that mice without p63 are born without skin and have malformed limbs. In humans, p63 mutations can cause cleft lips or other malformations of skin and teeth. Loss of p63 function is also associated with metastatic cancer in adults.

"We have known for a long time that this transcription factor is probably the most important for skin development. What we have not known is what it does," said Yi.

The researchers used fluorescent tags to illuminate the cells in which p63 was present. They then employed ATAC-seq and single-cell RNA-seq to examine patterns of gene expression. The team examined cells from days 9 to 13 of the 19-day mouse gestation, which is the gestational period in which skin forms.

The research team discovered that p63 could switch on at least 520 genes and ignite several critical signaling pathways. P63 can switch on the Wnt pathway critical for hair follicle formation, for example.

Specifically, p63 directly upregulates Wnt ligands, Frizzled receptors, and transcription errors to promote Wnt. P63 can also ignite the Notch pathway that prompts the differentiation of stem cells into the epidermis and the Eda pathway that controls the formation of hair follicles, teeth and sweat glands.

The scientists also discovered that the process started earlier than previously believed, and that the process affected the thousands of regions of the genome governing the formation of skin and limbs.

The study provides insight into the critical role p63 plays at the onset of skin development. Furthermore, the study may help explain how p63 mutations can cause so many skin diseases in humans.

The authors of the study stress the importance of further studies using human cells. Replication of the study could help guide researchers in the development of new prenatal tests and treatments for skin-related birth defects. Additional research could also shape development of new methods of getting adult cells to act more like embryonic cells, and new ways to generate fully functional human skin.

"Instead of just grafting a piece of skin to cover your body, you could regenerate it as if it were going through development for the first time," he said.

The researchers published their findings in the journal Developmental Cell.