KLF3 mediates epidermal differentiation through the epigenomic writer CBP [RNA-seq]

The differentiated layers of the epidermis protect the body from the outside environment. Impairments in the differentiation process can lead to skin diseases that can afflict ~20% of the population. Thus, it is of utmost importance to characterize and understand the factors that promote the differentiation process. Here we identify the transcription factor KLF3 as a novel regulator of epidermal differentiation. Knockdown of KLF3 results in reduced differentiation gene expression and increased cell cycle gene expression. Over 50% of KLF3’s genomic binding sites occur at regions containing H3K4me/H3K27ac with the vast majority at active enhancers. KLF3 bound to active enhancers proximal to differentiation genes that are dependent upon KLF3 for expression. Based on this association, we sought to investigate KLF3’s possible relationship with the enhancer associated proteins CBP and P300. Analysis of the transcriptome controlled by CBP and P300 showed that CBP and KLF3 control a similar gene expression program and are both essential for promoting differentiation. In addition, 35% of CBP’s genomic binding sites overlap with KLF3 and knockdown of KLF3 results in reduced CBP localization at enhancers proximal to differentiation gene clusters. Our results suggest that KLF3 regulates differentiation gene expression by promoting CBP localization at enhancers. KLF3 knockdown, KLF4 knockdown, KLF3/KLF4 double knockdown, CBP knockdown, and P300 knockdown RNA-seq in 3 day differentiated primary keratinocytes.