Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer

Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R.; Vuong, Linh; Chen, Gang; Briançon, Nadège; Bolotin, Eugene; Lytle, Christian; Nair, Meera G.; Sladek, Frances M.

doi:10.7554/elife.10903

Cited by 74 publications

(103 citation statements)

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“…PAX6 is a master regulator of pancreas development . In contrast, progressive overexpression of PAX6 contributes to colon carcinogenesis when P2‐HNF4α expression is either maintained or increased . Thus, PAX6 may play important roles in determining the tissue distribution and carcinogenic changes of P2‐HNF4α and HNF4A‐AS1 in the pancreas and intestine.…”

Section: Discussionmentioning

confidence: 99%

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Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Guo

Lü

2018

J of Cellular Biochemistry

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Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver, whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α. HNF4A-AS1, a long noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. Paired box 6 (PAX6), a master regulator of pancreas development overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4α mutants identified in patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer. Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1α and farnesoid X receptor, key regulators of insulin secretion. Taken together, our study provides novel mechanistic insights regarding the transcriptional regulation and transactivation activity of HNF4α in digestive tissues.

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Section: Discussionmentioning

confidence: 99%

“…Downregulation of P1‐HNF4α has been reported in hepatocellular carcinoma (HCC), colorectal carcinoma, and gastric carcinoma, during which P2 products are aberrantly elevated . P2‐HNF4α has been shown to promote inflammation and carcinogenesis in colon …”

Section: Introductionmentioning

confidence: 99%

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Guo

Lü

2018

J of Cellular Biochemistry

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“…Primary antibodies specific to P1- and P2-driven isoforms of HNF4A (R&D Systems) have been previously described (Chellappa et al., 2016) (Table S2). …”

Section: Methodsmentioning

confidence: 99%

TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors

et al. 2017

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SummaryUnderstanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryonic development, less is known about their roles at later stages of differentiation. Using an in vitro model of hepatocyte differentiation, we show here that 5hmC precedes the expression of promoter 1 (P1)-dependent isoforms of HNF4A, a master transcription factor of hepatocyte identity. 5hmC and HNF4A expression from P1 are dependent on ten-eleven translocation (TET) dioxygenases. In turn, the liver pioneer factor FOXA2 is necessary for TET1 binding to the P1 locus. Both FOXA2 and TETs are required for the 5hmC-related switch in HNF4A expression. The epigenetic event identified here may be a key step for the establishment of the hepatocyte program by HNF4A.

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“…The IEC-specific knockout of mouse Hnf4a results in spontaneous intestinal inflammation similar to human IBD (Darsigny et al 2009). In accord, genetic variants at human HNF4A are associated with risk for both UC and CD as well as colon cancer (Barrett et al 2009;Jostins et al 2012;Marcil et al 2012;Chellappa et al 2016). HNF4A is predicted to bind a majority of IBD-linked CRRs and to regulate IBD-linked genes (Haberman et al 2014;Meddens et al 2016).…”

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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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Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer

Cited by 74 publications

References 78 publications

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors

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

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