Hybrid Stomach-Intestinal Chromatin States Underlie Human Barrett’s Metaplasia

Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer

“…Barrett's esophagus (BE) and gastric intestinal metaplasia (GIM), closely related human disorders that precede gastric and esophageal adenocarcinomas ( Giroux and Rustgi 2017 ), almost always express CDX2 and other intestinal TFs ( Eda et al 2003 ; Groisman et al 2004 ; Lee et al 2012 ; Colleypriest et al 2017 ; Rogerson et al 2019 ; Nowicki-Osuch et al 2021 ). Recent evidence affirms the gastric origins of BE ( Nowicki-Osuch et al 2021 ; Singh et al 2021 ) and reinforce the view that BE and GIM are fundamentally similar conditions arising in the gastric cardia or antrum, respectively. Both BE ( Lavery et al 2014 ; McDonald et al 2015 ) and GIM ( Tsukamoto et al 2006 ; Correa et al 2010 ; Singh et al 2021 ) display mixed gastric and intestinal features, reflecting concomitant activation of stomach and intestinal enhancers with incomplete intestinal differentiation ( Singh et al 2021 ).…”

“…Recent evidence affirms the gastric origins of BE ( Nowicki-Osuch et al 2021 ; Singh et al 2021 ) and reinforce the view that BE and GIM are fundamentally similar conditions arising in the gastric cardia or antrum, respectively. Both BE ( Lavery et al 2014 ; McDonald et al 2015 ) and GIM ( Tsukamoto et al 2006 ; Correa et al 2010 ; Singh et al 2021 ) display mixed gastric and intestinal features, reflecting concomitant activation of stomach and intestinal enhancers with incomplete intestinal differentiation ( Singh et al 2021 ). Although ectopic CDX2 expression induces intestinal genes in mouse fetal stomachs ( Silberg et al 2002 ; Mutoh et al 2004 ), when endoderm fate is plastic ( Banerjee et al 2018 ), adult foregut epithelia are reported to resist CDX2-mediated intestinalization ( Stairs et al 2008 ; Kong et al 2011 ; Simmini et al 2014 ).…”

“…S4A ). Partial gains and losses of intestinal and gastric enhancer activity, respectively, in antral organoids mirror the mixed stomach–intestinal states described in human BE ( Van De Bovenkamp et al 2003 ; Lavery et al 2014 ) and GIM ( Tsukamoto et al 2006 ; Correa et al 2010 ; Singh et al 2021 ). Notably, CDX2 CnR revealed no binding at the gastric enhancers attenuated in stomach organoids ( Fig.…”

“…CDX2 is abundantly expressed in BE and GIM ( Liu et al 2007 ; Lee et al 2012 ; Singh et al 2021 ), and HNF4A, a TF expressed at low levels in adult stomachs, is up-regulated in both conditions ( Kojima et al 2006 ; Nowicki-Osuch et al 2021 ; Wang et al 2021 ). Transcriptional profiling of BE identifies CDX2 and HNF4A as prominent candidate regulators ( Supplemental Fig.…”

Adenocarcinoma of the oesophagus: is it gastric cancer?

“…By contrast, variants of GC that are more common in the non-cardia regions of the stomach including tumours with microsatellite instability, Epstein-Barr virus infection or the diffuse histologic type are less common in GCs localised to the cardia and in EAC. Genetic results from TCGA are consistent with recent epigenetic studies of BE relative to normal gastric and oesophageal tissues, which also demonstrated evidence for a gastric origin to BE 3. Furthermore, a recent study utilising comprehensive single-cell transcriptomic profiling, in silico lineage tracing, mutation analyses from human tissues spanning the proximal stomach to squamous oesophagus healthy and diseased donors, showed that BE originates from gastric cardia progenitors through distinct transcriptional programmes 4.…”