UC San Diego

The outermost layers of skin consist of stratified epithelia that serve as a barrier and interface to the outside environment. These epithelia are comprised primarily of keratinocytes, which exist as self-renewing progenitors in the innermost layer that differentiate into overlying protective layers. On a transcriptional level, keratinocyte differentiation involves coordinated induction and repression of hundreds of genes, but the genetic regulators governing this process are not fully understood. The homeodomain-only protein homeobox (HOPX) is known to be involved in keratinocyte differentiation, but prior studies disagree whether it promotes or inhibits this process. Here, we show that HOPX activates skin differentiation in primary human keratinocytes and organotypic epidermal tissue. HOPX expression is induced by the transcription factor ZNF750, which binds an enhancer located ~6 kb downstream of the 3’ end of the HOPX gene. Whole transcriptome analysis demonstrates that HOPX controls expression of 589 differentially expressed genes and is a positive regulator of late epidermal differentiation. These results show that HOPX functions downstream of ZNF750, a well-defined transcription factor in the skin that is activated by p63. In this context, we propose that HOPX functions within a p63-ZNF750-HOPX pathway to upregulate key proteins required for terminal epidermal differentiation, providing clarity to previous studies showing conflicting results. Future studies will aim to decipher the molecular pathways and mechanisms operating downstream of HOPX that engage the late differentiation program.