The Foxa family of transcription factors in development and metabolism

Friedman, Joshua R.; Kaestner, Klaus H.

doi:10.1007/s00018-006-6095-6

Cited by 440 publications

(393 citation statements)

References 130 publications

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“…Foxa2 is a member of the Foxa subfamily of winged‐helix/ forkhead box (Fox) transcription factors comprised of three unlinked genes ( Foxa1, Foxa2, and Foxa3 ) that share a highly conserved DNA‐binding domain (Friedman & Kaestner, 2006). The structure of Foxa forkhead box has been solved and resembles that of H1 histone (Clark, Halay, Lai & Burley, 1993).…”

Section: Introductionmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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Section: Introductionmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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“…Among them, members of the Foxa subfamily play important roles in early organ development and metabolism (24,25). We recently have shown that Forkhead box protein A3 (Foxa3), previously known to play a role in liver during long-term starvation and in pancreas development (26,27), is involved in the selective expansion of epididymal fat depots during a high-fat diet and in the suppression of energy expenditure during aging (28,29) and that its variants are associated with human metabolic traits (30).…”

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confidence: 99%

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

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“…Because so many current mouse models display extreme phenotypes or embryonic lethality, and heterozygotes are usually unaffected, mutations in genes, especially null mutations, do not seem sufficient to explain NTDs (Bell et al, 2003;Bulgakov et al, 2004;Finnell et al, 2002;Friedman and Kaestrer, 2006;Hatakeyama et al, 2004;Hirata et al, 2001;Mathers, 2005;Nagai et al, 2000;Pierani et al, 2001;Sahara et al, 2007;Tachibana et al, 2002;Xu et al, 1999). miRNAs may offer a more subtle deregulation, and there is enough evidence that miRNA genes are under regulation by methylation to add plausibility to the idea (Bak et al, 2008;Han et al, 2007;Lujambio et al, 2007;Weber et al, 2007).…”

Section: Conclusion: Future Directionsmentioning

confidence: 99%

A new perspective on neural tube defects: Folic acid and microRNA misexpression

Shookhoff

Gallicano

2010

Genesis

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Summary: Neural tube defects (NTDs) are the second most common birth defects in the United States. It is well known that folic acid supplementation decreases about 70% of all NTDs, although the mechanism by which this occurs is still relatively unknown. The current theory is that folic acid deficiency ultimately leads to depletion of the methyl pool, leaving critical genes unmethylated, and, in turn, their improper expression leads to failure of normal neural tube development. Recently, new studies in human cell lines have shown that folic acid deficiency and DNA hypomethylation can lead to misexpression of microRNAs (miRNAs). Misexpression of critical miRNAs during neural development may lead to a subtle effect on neural gene regulation, causing the sometimes mild to severely debilitating range of phenotypes exhibited in NTDs. This review seeks to cohesively integrate current information regarding folic acid deficiency, methylation cycles, neural development, and miRNAs to propose a potential model of NTD formation. In addition, we have examined the relevant gene pathways and miRNAs that are predicted to affect them, and based on our investigation, we have devised a basic template of experiments for exploring the idea that miRNA misregulation may be linked to folic acid deficiency and NTDs. genesis 48:282-294, 2010. V V C 2010 Wiley-Liss, Inc.

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The Foxa family of transcription factors in development and metabolism

Cited by 440 publications

References 130 publications

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

A new perspective on neural tube defects: Folic acid and microRNA misexpression

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