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

Abstract

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 Barretts 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 Barretts 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 Barretts metaplasia in the esophagus (BE) is a pre-neoplastic condition with no preclinical human models, these findings have a profound impact on the modeling Barretts metaplasia-in-a-dish. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/442930v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@8ce08aorg.highwire.dtl.DTLVardef@e98c83org.highwire.dtl.DTLVardef@107f521org.highwire.dtl.DTLVardef@16e7523_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIKeratinocytes transdifferentiate into the gut lineage upon depletion of SPT6 C_LIO_LISuch transdifferentiation recapitulates Barretts metaplasia, not the healthy gut C_LIO_LIAcid downregulates SPT6, which derails the expression and functions of TP63 C_LIO_LISuch downregulation precedes the metaplasia-dysplasia-neoplasia cascade C_LI