Skin Disorder Therapies Could Get Lift from Newly Discovered Molecule

Investigators at the University of Birmingham have discovered a protein that could hold the key to novel therapies for skin problems including psoriasis—a common, chronic skin disease that affects over 100 million people worldwide. The protein is a fragment of a larger molecule, called JARID2, which was previously believed to only be present in the developing embryo, where it coordinates the formation of tissues and organs. Findings from the new study were published online today in EMBO Journal through an article titled “A novel form of JARID2 is required for differentiation in lineage‐committed cells.”

University of Birmingham researchers found a shortened form of JARID2—called ΔN‐JARID2—in adult skin cells, and they showed it is responsible for ensuring these skin cells differentiate.

“In some diseases, cells lose their ability to differentiate and reproduce more rapidly. Being able to redirect cells back to their usual life cycle could alleviate the processes behind the disease,” explains senior study investigator Aditi Kanhere, Ph.D., a group leader at the University of Birmingham’s School of Biosciences.

The significance of this finding was immediately recognized by Dr. Kanhere’s team, which studies how gene expression is regulated in normal and diseased conditions.

“We show that, unlike in embryonic stem cells, in lineage‐committed human cells, including human epidermal keratinocytes, JARID2 predominantly exists as a novel low molecular weight form, which lacks the N‐terminal PRC2‐interacting domain (ΔN‐JARID2),” the authors write. “We show that ΔN‐JARID2 is a cleaved product of full‐length JARID2 spanning the C‐terminal conserved jumonji domains. JARID2 knockout in keratinocytes results in up‐regulation of cell cycle genes and repression of many epidermal differentiation genes.”

Interestingly, these new findings show that ΔN‐JARID2 is present in the skin layers, where it is responsible for ensuring that the tissues maintain their usual state of differentiation which is necessary to properly form skin layers.

“Surprisingly, repression of epidermal differentiation genes in JARID2‐null keratinocytes can be rescued by expression of ΔN‐JARID2 suggesting that, in contrast to PRC2, ΔN‐JARID2 promotes activation of differentiation genes,” the authors state. “We propose that a switch from expression of full‐length JARID2 to ΔN‐JARID2 is important for the up‐regulation differentiation genes.”

The discovery has caught the eye of the patenting team at the University of Birmingham Enterprise, who filed a broad-based patent covering the use of ΔN‐JARID2 in therapies aimed towards conditions caused by hyperproliferation of skin cells such as psoriasis.

The research team is now investigating how ΔN‐JARID2 is generated and its wider implication in disease, while the patenting team hopes that this discovery will ultimately lead to novel therapies for skin conditions.