SPT6 loss permits the transdifferentiation of keratinocytes into an intestinal fate that resembles Barrett's metaplasia

Daniella T Vo; MacKenzie R Fuller; Courtney Tindle; Mahitha Shree Anandachar; Soumita Das; Debashis Sahoo; Pradipta Ghosh

doi:10.1016/j.isci.2021.103121

SPT6 loss permits the transdifferentiation of keratinocytes into an intestinal fate that resembles Barrett's metaplasia

iScience. 2021 Sep 11;24(10):103121. doi: 10.1016/j.isci.2021.103121. eCollection 2021 Oct 22.

Authors

Daniella T Vo^{1

2}, MacKenzie R Fuller^{3

4}, Courtney Tindle^{3

4}, Mahitha Shree Anandachar⁵, Soumita Das^{4

5

6}, Debashis Sahoo^{1

2

6}, Pradipta Ghosh^{3

4

6

7}

Affiliations

¹ Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0703, Leichtag Building 132, La Jolla, CA 92093-0703, USA.
² Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, La Jolla, USA.
³ Departments of Medicine and Cell and Molecular Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 232, La Jolla, CA 92093, USA.
⁴ HUMANOID Center of Research Excellence (CoRE), University of California San Diego, La Jolla, USA.
⁵ Department of Pathology, University of California San Diego, 9500 Gilman Drive, George E. Palade Bldg, Rm 256, La Jolla, CA 92093, USA.
⁶ Moore Comprehensive Cancer Center, University of California San Diego, La Jolla, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, USA.

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 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 potentially 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 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.

Keywords: Bioinformatics; Cell biology; Molecular biology.

Abstract

Grants and funding