Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

Halpern, Keren Bahar; Vana, Tal; Walker, Michael D.

doi:10.1074/jbc.m114.573469

Cited by 97 publications

(65 citation statements)

References 45 publications

(39 reference statements)

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“…In contrast, the present data suggest that DNMT3A acts as a positive regulator of Gbx2 and Pax2, either directly or indirectly. A similar mechanism has been described for FoxA2 activation during endoderm development (Bahar Halpern et al, 2014). This study hypothesized that in undifferentiated hESC-derived early endoderm-stage cells, low DNA methylation of certain CpG islands enabled binding of repressive proteins.…”

Section: Discussionsupporting

confidence: 59%

“…Methylation of CpG sites in the promoter region of a gene is thought to inhibit its expression, as shown in cancer and stem cells (Altun et al, 2010; Miranda and Jones, 2007; Momparler and Bovenzi, 2000). In some cases, DNMTs are also thought to activate gene expression by directly methylating gene bodies (Ball et al, 2009; Lister et al, 2009) or by inhibiting binding of repressors via methylation (Bahar Halpern et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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The epigenetic modifier DNMT3A is necessary for proper otic placode formation

Roellig

Bronner‐Fraser

2016

Developmental Biology

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Cranial placodes are thickenings in the ectoderm that give rise to sensory organs and peripheral ganglia of the vertebrate head. At gastrula and neurula stages, placodal precursors are intermingled in the neural plate border with future neural and neural crest cells. Here, we show that the epigenetic modifier, DNA methyl transferase (DNMT) 3A, expressed in the neural plate border region, influences development of the otic placode which will contribute to the ear. DNMT3A is expressed in the presumptive otic region at gastrula through neurula stages and later in the otic placode itself. Whereas neural plate border and non-neural ectoderm markers Erni, Dlx5, Msx1 and Six1 are unaltered, DNMT3A loss of function leads to early reduction in the expression of the key otic placode specifier genes Pax2 and Gbx2 and later otic markers Sox10 and Soho1. Reduction of Gbx2 was first observed at HH7, well before loss of other otic markers. Later, this translates to significant reduction in the size of the otic vesicle. Based on these results, we propose that DNMT3A is important for enabling the activation of Gbx2 expression, necessary for normal development of the inner ear.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

The epigenetic modifier DNMT3A is necessary for proper otic placode formation

Roellig

Bronner‐Fraser

2016

Developmental Biology

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“…Although greater methylation often defines lower transcriptional activity at the enhancer and proximal promoter, methylation can also maintain high expression of genes during development of both the nervous system and the endoderm 40 . Our study further revealed that Dnmt3a promoted transcription by antagonizing repressive histone modification upstream of the Hdac9 locus during an innate immune response.…”

Section: Discussionmentioning

confidence: 99%

Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

et al. 2016

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“…Methylation of CpG resides upstream of FOXA2 has been shown to correlate with expression in mouse endodermal development of pancreatic beta cells 27 . We therefore evaluated promoter methylation in four CpG islands in the FOXA2 promoter region (Fig.3A-B).…”

Section: Resultsmentioning

confidence: 99%

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role

Smith

Neff

Cohn

et al. 2016

Gynecologic Oncology

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BACKGROUND Forkhead box protein A2 (FOXA2) plays an important in development, cellular metabolism and tumorigenesis. The Cancer Genome Atlas (TCGA) identified a modest frequency of FOXA2 mutations in endometrioid endometrial cancers (EEC). The current study sought to determine the relationship between FOXA2 mutation and clinicopathologic features in EEC and FOXA2 expression. METHODS Polymerase chain reaction (PCR) amplification and sequencing were used to identify mutations in 542 EEC. Western blot, quantitative reverse transcriptase PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess expression. Methylation analysis was performed using combined bisulfite restriction analysis (COBRA) and sequencing. Chi-squared, Fisher's exact, student's t- and log-rank tests were performed. RESULTS Fifty-one mutations were identified in 49 tumors (9.4% mutation rate). The majority of mutations were novel, loss of function (LOF) (78.4%) mutations, and most disrupted the DNA-binding domain (58.8%). Six recurrent mutations were identified. Only two tumors had two mutations and there was no evidence for FOXA2 allelic loss. Mutation status was associated with tumor grade and not associated with survival outcomes. Methylation of the FOXA2 promoter region was highly variable. Most tumors expressed FOXA2 at both the mRNA and protein level. In those tumors with mutations, the majority of cases expressed both alleles. CONCLUSION FOXA2 is frequently mutated in EEC. The pattern of FOXA2 mutations and expression in tumors suggests complex regulation and a haploinsufficient or dominant-negative tumor suppressor function. In vitro studies may shed light on how mutations in FOXA2 affect FOXA2 pioneer and/or transcription factor functions in EEC.

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Paradoxical Role of DNA Methylation in Activation of FoxA2 Gene Expression during Endoderm Development

Cited by 97 publications

References 45 publications

The epigenetic modifier DNMT3A is necessary for proper otic placode formation

The epigenetic modifier DNMT3A is necessary for proper otic placode formation

Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role

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