A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity

Chen, Lei; Toke, Natalie H.; Luo, Shirley; Vasoya, Roshan P.; Fullem, Robert; Parthasarathy, Aditya; Perekatt, Ansu O.; Verzi, Michael P.

doi:10.1038/s41588-019-0384-0

Cited by 124 publications

(246 citation statements)

References 57 publications

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“…BMP signals control intestinal villus patterning (Walton et al, 2016b) and intestinal looping (Nerurkar et al, 2017), but the functions and mechanisms of BMP signals in villus maturation are not fully explored. In a recent study, we identified a reinforcing feed-forward loop of BMP/SMAD signaling and HNF4, which promotes and stabilizes enterocyte cell identity in the adult intestine (Chen et al, 2019). Future studies could also investigate the presence of this reinforcing loop of BMP/ SMAD signaling and HNF4 in the developing gut, and whether it promotes the maturation of the developing intestine or stabilization of mature transcription factor networks.…”

Section: Discussionmentioning

confidence: 93%

“…To test the function of HNF4 in the developing gut, we inactivated conditional alleles of Hnf4a (Hayhurst et al, 2001) in the gut endoderm using the Shh-Cre driver (Harfe et al, 2004), which is activated in the intestinal epithelium starting at ∼E9.5. We also examined germline null embryos lacking Hnf4g mediated by CRISPR knockout (Chen et al, 2019), and embryos with both HNF4 paralogs simultaneously deleted (hereafter referred to Hnf4α KO , Hnf4γ KO and Hnf4αγ DKO ; Fig. S1E,F).…”

Section: Hnf4 Factors Are Dispensable For Intestinal Specification Anmentioning

confidence: 99%

“…HNF4A binding activity is modulated by the microbiome (Davison et al, 2017) and suppressed in a mouse model of ulcerative colitis (Chahar et al, 2014). We recently demonstrated that HNF4A and HNF4G redundantly drive enterocyte identity in adult tissues (Chen et al, 2019). Although HNF4 transcription factors have been studied in a number of developmental contexts, their redundant functions have not been assayed in the context of the developing gut.…”

Section: Introductionmentioning

confidence: 99%

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HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine

et al. 2019

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As embryos mature, cells undergo remarkable transitions that are accompanied by shifts in transcription factor regulatory networks. Mechanisms driving developmental transitions are incompletely understood. The embryonic intestine transitions from a rapidly proliferating tube with pseudostratified epithelium prior to murine embryonic day (E) 14.5 to an exquisitely folded columnar epithelium in fetal stages. We sought to identify factors driving mouse fetal intestinal maturation by mining chromatin accessibility data for transcription factor motifs. ATAC-seq accessible regions shift during tissue maturation, with CDX2 transcription factor motifs abundant at chromatin-accessible regions of the embryo. Hepatocyte nuclear factor 4 (HNF4) transcription factor motifs are the most abundant in the fetal stages (>E16.5). Genetic inactivation of Hnf4a and its paralog Hnf4g revealed that HNF4 factors are redundantly required for fetal maturation. CDX2 binds to and activates Hnf4 gene loci to elevate HNF4 expression at fetal stages. HNF4 and CDX2 transcription factors then occupy shared genomic regulatory sites to promote chromatin accessibility and gene expression in the maturing intestine. Thus, HNF4 paralogs are key components of an intestinal transcription factor network shift during the embryonic to fetal transition.

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Section: Discussionmentioning

confidence: 93%

Section: Hnf4 Factors Are Dispensable For Intestinal Specification Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine

et al. 2019

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“…Functionally, HNF4A plays a role in normal development of the liver[43–45], kidney[46], and intestine[47, 48]. In cancer biology, HNF4A has opposite roles in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Pan

Silva

Gull

et al. 2019

Preprint

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AbstractBackgroundsGastrointestinal adenocarcinomas (GIACs) of the tubular GI tract including esophagus, stomach, colon and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIACs are less well-characterized.We applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks using 907 GIAC samples from The Cancer Genome Atlas (TCGA). Complementary epigenomic technologies were performed to investigate HNF4A activation, including Circularized Chromosome Conformation Capture (4C), Chromatin immunoprecipitation (ChIP) sequencing, Whole Genome Bisulfite Sequencing (WGBS), and Assay for Transposase-Accessible Chromatin (ATAC) sequencing. In vitro and in vivo cellular phenotypical assays were conducted to study HNF4A functions.ResultsWe identified a list of functionally hyperactive master regulator (MR)TFs shared across different GIACs. As the top candidate, HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. We further characterized a complex interplay between HNF4A promoter and three distal enhancer elements, which was coordinated by GIAC-specific MRTFs including ELF3, GATA4, GATA6 and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptionally activating many downstream targets including HNF1A and factors of Interleukin signaling in a lineage-specific manner.ConclusionWe use a large cohort of patient samples and an unbiased mathematical approach to highlight lineage-specific oncogenic MRTFs, which provide new insights into the GIAC-specific gene regulatory networks, and identify potential therapeutic strategies against these common cancers.

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“…Foxa1, which drives EEC differentiation, is most highly expressed with the greatest degree of motif accessibility in Sox9 high cells and Hnf4g, which drives absorptive differentiation, is most highly expressed with the greatest degree of motif accessibility in Sox9 neg cells ( Fig. 3C) (Chen et al, 2019;Ye and Kaestner, 2009). We also observed several cases where TF expression and motif accessibility were inversely correlated.…”

Section: Chromatin Dynamics Are Linked To Transcription Factor Networkmentioning

confidence: 99%

Quantitative classification of chromatin dynamics reveals regulators of intestinal stem cell differentiation

Raab

Tulasi

Wager

et al. 2019

Preprint

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Intestinal stem cell (ISC) plasticity is thought to be regulated by broadly-permissive chromatin shared between ISCs and their progeny. Here, we utilize a Sox9 EGFP reporter to examine chromatin across ISC differentiation. We find that open chromatin regions (OCRs) can be defined as broadly-permissive or dynamic in a locus-specific manner, with dynamic OCRs found primarily in loci consistent with distal enhancers. By integrating gene expression with chromatin accessibility at transcription factor (TF) motifs in context of Sox9 EGFP populations, we classify broadly-permissive and dynamic chromatin relative to TF usage. These analyses identify known and potential regulators of ISC differentiation via their association with dynamic changes in chromatin. We observe ISC expansion in Id3-null mice, consistent with computational predictions. Finally, we examine the relationship between gene expression and 5hydroxymethylcytosine (5hmC) in Sox9 EGFP populations, which reveals 5hmC enrichment in absorptive lineage specific genes. Our data demonstrate that intestinal chromatin dynamics can be quantitatively defined in a locus-specific manner, identify novel potential regulators of ISC differentiation, and provide a chromatin roadmap for further dissecting the role of cis regulation of cell fate in the intestine. Tetteh et al., 2016). The genetic mechanisms that allow IECs to adopt metastable differentiated fates while exhibiting facultative ISC function are not fully understood.Chromatin landscapes consist of histone post-translational modifications, DNA modifications, and higher-order structural organization, and are known to exert regulatory control on cell fate.

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A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity

Cited by 124 publications

References 57 publications

HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine

HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine

Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Quantitative classification of chromatin dynamics reveals regulators of intestinal stem cell differentiation

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