SUMMARY Transient depletion of the transcription elongation factor SPT6 in the keratinocyte has been recently shown to inhibit epidermal differentiation and stratification; instead, they transdifferentiate into a gut-like lineage. We show here that this phenomenon of transdifferentiation recapitulates Barrett’s metaplasia, the only human pathophysiologic condition in which a stratified squamous epithelium that is injured due to chronic acid reflux is trans-committed into an intestinal fate. The evidence we present here not only lend support to the notion that the keratinocytes are the cell of origin of Barrett’s metaplasia, but also provide mechanistic insights linking transient acid exposure, downregulation of SPT6, stalled transcription of the master regulator of epidermal fate TP63, loss of epidermal fate and metaplastic progression. Because Barrett’s metaplasia in the esophagus (BE) is a pre-neoplastic condition with no preclinical human models, these findings have a profound impact on the modeling Barrett’s metaplasia-in-a-dish. GRAPHIC ABSTRACT HIGHLIGHTS Keratinocytes transdifferentiate into the gut lineage upon depletion of SPT6 Such transdifferentiation recapitulates Barrett’s metaplasia, not the healthy gut Acid downregulates SPT6, which derails the expression and functions of TP63 Such downregulation precedes the metaplasia-dysplasia-neoplasia cascade

SPT6 loss Permits the Transdifferentiation of Keratinocytes into an Intestinal Fate that Recapitulates Barrett’s Metaplasia