An international research team reports that it has found that Polycomb complexes are essential for proper skin development. This latest discovery could improve development of future stem cell therapies to generate “skin on a dish” to transplant into burn victims and patients with skin-blistering disorders, according to the scientists, who published their study “Polycomb complexes redundantly maintain epidermal stem cell identity during development” in Genes & Development.

“Polycomb repressive complex 1 (PRC1) and PRC2 are critical epigenetic developmental regulators. PRC1 and PRC2 largely overlap in their genomic binding and cooperate to establish repressive chromatin domains demarcated by H2AK119ub and H3K27me3. However, the functional contribution of each complex to gene repression has been a subject of debate, and understanding of its physiological significance requires further studies,” write the investigators.

“Here, using the developing murine epidermis as a paradigm, we uncovered a previously unappreciated functional redundancy between Polycomb complexes. Coablation of PRC1 and PRC2 in embryonic epidermal progenitors resulted in severe defects in epidermal stratification, a phenotype not observed in the single PRC1-null or PRC2-null epidermis. Molecular dissection indicated a loss of epidermal identity that was coupled to a strong derepression of nonlineage transcription factors, otherwise repressed by either PRC1 or PRC2 in the absence of its counterpart. Ectopic expression of subsets of PRC1/2-repressed nonepidermal transcription factors in wild-type epidermal stem cells was sufficient to suppress epidermal identity genes, highlighting the importance of functional redundancy between PRC1 and PRC2.

“Altogether, our studies show how PRC1 and PRC2 function as two independent counterparts, thereby providing a repressive safety net that protects and preserves lineage identity.”

Polycomb complexes are groups of proteins that maintain the gene-expression patterns during early development by regulating the structure of DNA and proteins in cells. They play a critical role in the repression of gene expression to help control responses to changing environments and stimuli.

The researchers found that Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2) each help maintain the skin-specific gene expression pattern necessary for proper development of the skin. The team studied Polycomb complexes in the developing skin of mice that were bred missing either Polycomb complex but still had a functioning skin barrier, albeit with minor defects in skin thickness.

In contrast, when researchers bred mice missing both complexes, it resulted in severe skin defects including a significantly thin epidermis that lacked essential layers required for survival. The researchers found that PRC1 and PRC2 help maintain regular function of gene repression, in particular the repression of transcription factors essential for the formation of non-skin tissues.

“We show that Polycomb complexes function redundantly to control proper development of the skin,” said the study’s corresponding author Elena Ezhkova, PhD, professor of cell, developmental and regenerative biology, and dermatology in the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai in New York. “Polycomb complexes function together to repress non-skin lineage programs and thus control proper skin development.”

Since researchers have established that both Polycomb complexes are vital for skin formation, this discovery could improve current protocols for generating skin cells from stem cells. Polycomb complexes are also often overexpressed in epithelial cancers, including skin cancers. Treatments using Polycomb inhibitors are currently being studied in clinical trials. This study suggests that parallel inhibition, use of both PRC1 and PRC2 inhibitors, may be a more powerful form of treatment for cancer patients.

While Polycomb complexes are important for skin function, their role in other tissues remains unknown. Future studies should explore the role of Polycomb complexes in developing and regenerating tissues, the scientists said.

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