Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction with Transcription Factor CDX2

Roman, Adrianna K. San; Aronson, Boaz E.; Krasinski, Stephen D.; Shivdasani, Ramesh A.; Verzi, Michael P.

doi:10.1074/jbc.m114.620211

Cited by 68 publications

(78 citation statements)

References 46 publications

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“…The CDX2 motif was strongly enriched in both groups of binding regions, but whereas Hindgutenriched sites were enriched in NANOG and SOX15 motifs, consistent with a role for SOX factors supporting endoderm development (Kanai-Azuma et al, 2002), Adult-enriched regions were most enriched in HNF4A motifs ( Fig. 2D, Table S1), consistent with the function of HNF4 in the mature intestine (Babeu et al, 2009;Cattin et al, 2009;San Roman et al, 2015;Stegmann et al, 2006). Examples of Hindgut-enriched target genes included the HOXB cluster genes ( Fig.…”

Section: Cdx2 Regulates Distinct Transcriptional Targets Across Humansupporting

confidence: 62%

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The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

Kumar¹,

Tsai²,

Chen³

et al. 2018

Preprint

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Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic-loss of CDX2 triggers homeotic transformation of intestinal fate, while adult-onset Cdx2-loss compromises critical physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-offunction phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities.Thus, CDX2 is not sufficient to activate a mature intestinal program, but rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or maturity. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

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Section: Cdx2 Regulates Distinct Transcriptional Targets Across Humansupporting

confidence: 62%

“…Low Input mRNA library kit (Clonetech SMARTer 634888). Adult RNA data were curated from GSE70766 and GSE98724 (San Roman et al, 2015;Saxena et al, 2017).…”

Section: Rna-seqmentioning

confidence: 99%

The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

Kumar¹,

Tsai²,

Chen³

et al. 2018

Preprint

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“…5G). These transcription factors have all been shown to play a role in intestinal development (Verzi et al, 2010;Beuling et al, 2012;Kerschner et al, 2014;Walker et al, 2014;Gosalia et al, 2015;San Roman et al, 2015;Yang et al, 2016), suggesting that Barrett's and OAC cells have reverted to a more primitive state where these factors are operational. For example, HNF4A, GATA6 and FOXA3 are all broadly expressed in the stomach, liver, pancreas and intestine during mouse embryogenesis but are absent from the oesophagus (Sherwood et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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

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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...

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“…Although the Y1H assay demonstrated that all three zebrafish Hnf4 members are capable of binding in3.4, we concentrated our efforts on understanding the function of Hnf4a because it is the most highly conserved Hnf4 family member (Supplemental Fig. S1G; Supplemental Table S10) and has well-documented roles in intestinal physiology (San Roman et al 2015). To that end, we generated hnf4a mutant zebrafish using the CRISPR/Cas9 system ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

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Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction with Transcription Factor CDX2

Cited by 68 publications

References 46 publications

The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

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

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

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