Evidence for local control of gene expression in the epidermal differentiation complex

The epidermal differentiation complex (EDC), located on chromosomal band 1q21, consists of at least 43 genes that are expressed during keratinocyte differentiation. Indicative of a role for chromatin structure in tissue specificity of EDC gene expression, we identified an inverse correlation between expression and DNA methylation for two EDC genes (S100A2 and S00A6) in human keratinocytes and fibroblasts. 5-azacytidine (5AC) and sodium butyrate (NaB) are two agents known to promote 'open' chromatin structure. To explore the relationship between chromatin structure and keratinocyte differentiation, we treated normal human keratinocytes (NHK) with 5AC or NaB, or with protocols known to promote their terminal differentiation. We then measured the steady-state mRNA levels for several S100 genes, small proline rich region-1, -2, and -3, loricrin, and involucrin by Northern blotting. 5AC and NaB each markedly increased expression of SPRR1/2 and involucrin in NHK. In contrast, expression of S100A2 was reduced by both agents, and by induction of keratinocyte differentiation. Moreover, while the clustered EDC genes displayed a general tendency to be expressed in epithelial cells, they displayed different patterns of cell type-specific expression. These results indicate that local, gene-specific factors play an important role in the regulation of EDC gene expression in the keratinocyte lineage and during keratinocyte terminal differentiation.