SPT6 Promotes Epidermal Differentiation and Blockade of an Intestinal Phenotype through Control of Transcriptional Elongation

In adult tissue, stem and progenitor cells must tightly regulate the balance between proliferation and differentiation to sustain homeostasis. It is assumed that the rate-limiting step during the induction of somatic tissue differentiation is the recruitment of RNA polymerase II (Pol II) to promoters. Here we show that ~30% of induced differentiation genes already contain stalled Pol II at the promoters in epidermal stem and progenitor cells which is then released into productive transcription elongation upon differentiation. Central to this process is the histone chaperone, SPT6 which is necessary for the elongation of these differentiation genes. Upon SPT6 depletion there is a loss of human skin differentiation and stratification. Unexpectedly, loss of SPT6 also caused the spontaneous transdifferentiation of epidermal cells into an intestinal phenotype due to the stalled transcription of the master regulator of epidermal fate P63. Our findings suggest that control of transcription elongation through SPT6 plays a prominent role in adult somatic tissue differentiation and the inhibition of alternative cell fate choices. RNA-seq of SPT6 knockdown in regenerated epidermis using organotypic culture. ChIP-seq with SPT6 and RNA Pol II antibodies in differentiated primary keratinocytes, ATAC-seq in differentiated primary keratinocytes.