Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium

Colleypriest, Benjamin J.; Burke, Zoë D.; Griffiths, Leonard P.; Chen, Yu; Yu, Wei-Yuan; Jover, Ramiro; Bock, Michael; Biddlestone, L.; Quinlan, Jonathan M.; Ward, Stephen G.; Farrant, J. Mark; Slack, Jonathan; Tosh, David

doi:10.1016/j.diff.2016.11.001

Cited by 23 publications

(20 citation statements)

References 53 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is important to emphasize that HNF4A is insufficient to drive the opening of all the newly accessible regions in Barrett's cells. Nevertheless, these results are consistent with the observation that HNF4A overexpression in mouse esophageal epithe-lial cells is sufficient to induce the expression of several Barrett'sspecific markers (Colleypriest et al 2017). This activity of HNF4A is akin to pioneering activity that has been demonstrated for several transcription factors (Zaret and Carroll 2011).…”

Section: Discussionsupporting

confidence: 90%

Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

et al. 2019

View full text Add to dashboard Cite

Esophageal adenocarcinoma (EAC) is one of the most frequent causes of cancer death, and yet compared to other common cancers, we know relatively little about the molecular composition of this tumor type. To further our understanding of this cancer, we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in EAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centered on HNF4A and GATA6. These transcription factors work together to control the EAC transcriptome. We show that this network is activated in Barrett's esophagus, the putative precursor state to EAC, thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorize EAC at a genome scale and implicate HNF4A activation as a potential pivotal event in its malignant transition from healthy cells.Corresponding authors: andrew.d.sharrocks@manchester.ac.uk, yeng.ang@srft.nhs.uk Article published online before print. Article, supplemental material, and publication date are at

show abstract

Section: Discussionsupporting

confidence: 90%

Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

et al. 2019

View full text Add to dashboard Cite

show abstract

“…It is currently unclear how this network is initially established but we demonstrate that HNF4A is able to penetrate and open up regions of inaccessible chromatin which may represent one of the initiating events for Barrett's development. Indeed, these results are consistent with the observation that HNF4A over-expression in mouse oesophageal epithelial cells is sufficient to induce the expression of several Barrett's-specific markers (Colleypriest et al, 2017). This activity of HNF4A is akin to pioneering activity which has been demonstrated for several transcription factors (Zaret and Carroll, 2011).…”

Section: Discussionsupporting

confidence: 90%

“…Furthermore, HNF4A has previously been implicated in the initial response of normal human oesophageal mucosa to bile acids (Green et al, 2014). More recently, HNF4A has been shown to be sufficient to induce a columnar-like phenotype in adult mouse oesophageal epithelium (Colleypriest et al, 2017). These results suggest that HNF1A/B and HNF4A may play an initiating role in promoting the transition to Barrett's in human disease.…”

Section: Discussionmentioning

confidence: 87%

Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state

Rogerson

Britton

Withey

et al. 2018

Preprint

View full text Add to dashboard Cite

Running title: Barrett's oesophagus and OAC share a primitive intestinal transcription factor network. AbstractOesophageal adenocarcinoma (OAC) is one of the most frequent causes of cancer deaths and yet compared to other common cancers, we know relatively little about the molecular composition of this tumour type. To further our understanding of this cancer we have used open chromatin profiling to decipher the transcriptional regulatory networks that are operational in OAC. We have uncovered a transcription factor network that is usually found in primitive intestinal cells during embryonic development, centred on HNF4A and GATA6. These transcription factors work together to control the OAC transcriptome. Importantly, we show that this network is activated in Barrett's oesophagus, the putative precursor state to OAC thereby providing novel molecular evidence in support of stepwise malignant transition. Furthermore, we show that HNF4A alone, is sufficient to drive chromatin opening and activation of a Barrett's-like chromatin signature when expressed in normal human epithelial cells. Collectively, these data provide a new way to categorise OAC at a genome scale and implicate HNF4A activation as a potential pivotal event in regulating its malignant transition from healthy cells. Results Identification of a network of transcription factors active in OACPreviously we used ATAC-seq to profile the open chromatin landscape of OAC cell lines and identified AP1 as an important transcription factor family in controlling the transcriptional networks in OAC . To further interrogate the transcriptional networks operating in OAC, we decided to take an alternative approach, starting with clearly defined open chromatin datasets from OAC patient samples rather than a diverse set of OAC-derived cell lines. We previously validated our cell line-derived results by profiling the open chromatin of six patient-derived biopsies but this revealed two distinct subclusters of OAC samples based on their open chromatin landscapes; one that clustered with normal samples and one that was unique . We revisited this issue by performing subclustering by PCA analysis following the addition of an additional paired normal and OAC dataset and again we observed a clear partitioning of samples ( Supplementary Fig. S1A). We therefore re-focussed our attention on the four OAC samples which are clearly distinct from the normal samples (T_002, T_003, T_005, T_006; Supplementary Fig. S1A).To derive a unified dataset of open chromatin regions in oesophageal-derived tissue, we combined all the ATAC-seq data from three normal oesophageal tissue samples (matched with T_003, T_005 and T_006) and these four OAC samples and recalled the open accessible chromatin regions from this combined data. We selected the top 50,000 open regions ( Supplementary Table S1A) and found that these were roughly equally divided between promoter-proximal, intragenic and intergenic regions (Fig. 1A). PCA analysis based on these peaks confirmed the distinct clustering of the normal an...

show abstract

“…[24] Finally, overexpression of HNF4A and FOXA2 in squamous cells also induces expression of columnar type transcripts and proteins including cytokeratins, villin, trefoil factor, and mucins. [14,25] On the other hand, loss of key squamous type transcription factors, including p63 and SOX2, has been shown to cause columnar metaplasia in mice. For example, embryos lacking p63 develop a BE-like metaplasia, and hypomorphic SOX2 mutants also develop regional columnar metaplasia in the esophagus and forestomach.…”

Section: Introductionmentioning

confidence: 99%

GATA4, expressed in Barrett’s esophagus and esophageal adenocarcinoma, can block squamous epithelial cell gene expression in human esophageal cells

Stavniichuk

DeLaForest

Thompson

et al. 2020

Preprint

View full text Add to dashboard Cite

Metaplasia often involves a change from one cell type to another that was present during organogenesis. The embryonic esophagus is initially lined by columnar cells that are replaced by squamous cells, and metaplasia in Barrett's esophagus (BE) involves a change from squamous to columnar cells in the setting of gastroesophageal reflux.Here, we explored the effect of ectopic expression of the essential developmental transcription factor GATA4 on squamous epithelial cell gene expression using human esophageal squamous epithelial cells. We found that GATA4 protein, although absent in mature human esophageal squamous epithelium, was present in BE and esophageal adenocarcinoma (EAC). Moreover, acid and bile induced GATA4 mRNA in esophageal squamous epithelial cells. Ectopic GATA4 expression in esophageal squamous epithelial cells generally compromised squamous cell marker gene expression, although the extent varied between cell lines studied. We observed GATA4 occupancy in the p63, KRT5, and KRT15 gene promoters, suggesting that GATA4 can directly repress expression of typical squamous epithelial cell marker genes. Overall, our data suggest a mechanism whereby GATA4 expression in abnormal esophageal cells, possibly induced by reflux, supports a columnar metaplastic cell identity by repressing expression of key genes required to program stratified squamous epithelial cell identity.

show abstract

Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium

Cited by 23 publications

References 53 publications

Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

Identification of a primitive intestinal transcription factor network shared between oesophageal adenocarcinoma and its pre-cancerous precursor state

GATA4, expressed in Barrett’s esophagus and esophageal adenocarcinoma, can block squamous epithelial cell gene expression in human esophageal cells

Contact Info

Product

Resources

About