Spatial polarity of the genome in the human epidermis

The spatial organization of the eukaryotic genome is non-random and related to nuclear function. Whether the localization of genes within the nucleus are related to the location of the proteins they encode within the cell remains to be understood. Here, we tested the relationship between genes that encode hemidesmosome (HD) components and their protein products during epidermal differentiation. In in vitro-generated raft cultures that recapitulate epidermal differentiation, we find that HD genes are positioned towards the basal side of the nucleus in basal progenitor cells where these genes are highly expressed, but not in differentiated suprabasal cells where these genes are transcriptionally repressed. Furthermore, promoting cell migration in these raft cultures causes a dynamic re-localization of these genes towards the leading edge of the nucleus in cells at the leading edge where these genes are induced. We find that the LINC complex and the physical attachment of the rafts to their underlying substrates are necessary for gene polarity. Finally, we find that the mRNA of one of these HD genes, ITGB4, is polarized towards the basal side of the cell where the protein product resides, and that disrupting the LINC complex causes mislocalization of ITGB4 mRNA and misregulation of HD transcription. These results demonstrate, to our knowledge, the first known example of gene polarity.