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Regulation and Funktion des Forkhead Transkriptionsfaktors FoxA1/2 im Stoffwechsel

English title Regulation and function of forkhead transcription factors A1 and A2 in metabolism
Applicant Stoffel Markus
Number 141209
Funding scheme Project funding (Div. I-III)
Research institution Molekulare Gesundheitswissenschaften Departement Biologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Physiology : other topics
Start/End 01.04.2012 - 31.03.2015
Approved amount 930'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Endocrinology

Keywords (4)

gene expression; transcription factor; liver metabolism; diabetes

Lay Summary (English)

Lead
Lay summary

The forkhead family of transcription factors of the Family A (formerly known as hepatocyte nuclear factors 3) in mammals includes three genes designated as Foxa1 (HNF-3a), Foxa2 (HNF-3β) and Foxa3 (HNF-3γ), which have overlapping patterns of tissue expression, including gut, central nervous system, neuroendocrine cells, and lung. They are all characterized by a 100 amino acid long, highly conserved winged helix motif that is responsible for monomeric recognition of specific DNA target sites, and is similar in structure to that of the linker histone H5. However, in contrast to linker histones that compact DNA in chromatin and repress gene expression, FoxA proteins are associated with transcriptionally active chromatin and may decompact DNA from the nucleosome.

FoxA factors have been shown to play crucial roles in organogenesis and cell differentiation during development. FoxA2, the earliest expressed forkhead, is essential for the development of the foregut endoderm and the notochord, a structure essential for sonic hedgehog signaling to pattern the neural tube. FoxA proteins are well positioned to regulate early gene expression because they can replace linker histones and affect chromatin structure directly and facilitate the binding of other nuclear receptors in a context dependent manner to their respective targets and hence initiate organ specific transcription factors. The unique ability of FoxA proteins to engage chromatin before other transcription factors has led to the concept that they act as “pioneer factors”.

Our group was the first to demonstrate that the activity of the FoxA family of transcription factors is regulated by extracellular signaling events. Specifically, we demonstrated that insulin signaling inactivates FoxA2 by specific phosphorylation of T156, which leads to the inactivation due to nuclear exclusion. We also demonstrated that Foxa2 functions as an “insulin sensor” in the liver and in the lateral hypothalamus. In the liver, Foxa2 is a key regulator of hepatic gene expression in response to fasting and feeding. Foxa2 is active in the fasted state promoting the expression of β-oxidation and ketogenic genes and inactive during feeding, when Foxa2 is inhibited in a phosphorylation-dependent manner via the insulin-PI3K-Akt signaling. In addition, FoxA2 activates the expression of microsomal transfer protein (Mttp), thereby increasing VLDL secretion and hepatic triglyceride export.  Furthermore, we have shown that FoxA2 is a potent transcriptional activator of apolipoprotein M (apoM), a critical component of preb-HDL and mature HDL, which has been shown in mice to protect against atherosclerotic plaque formation due to augmented reverse cholesterol transport.

In the current grant proposal we will study the role of post translational modifications in response to hormonal and metabolic stress on the activity and function of Foxa-1 and -2. Specifically, we will biochemically characterize these modifications in Foxa1 and FoxA2 and study the physiological role in pancreatic beta-cells, liver, and hypothalamus in mice. We will also elucidate the effect of these modifications on longevity, since genetic studies in flies suggest that forkhead transcription factors regulate lifespan. Together, this research will shed light on the molecular mechanisms by which FoxA2 activity and downstream effector pathways are regulated and how they modify metabolic stress and diseases such as obesity and type 2 diabetes.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
Ahmed Kashan, LaPierre Mary P., Gasser Emanuel, Denzler Rémy, Yang Yinjie, Rülicke Thomas, Kero Jukka, Latreille Mathieu, Stoffel Markus (2017), Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility, in Journal of Clinical Investigation, 127(3), 1061-1074.
Foxa1 is essential for development and functional integrity of the subthalamic nucleus
Gasser Emanuel, Johannssen Helge C., Rülicke Thomas, Zeilhofer Hanns Ulrich, Stoffel Markus (2016), Foxa1 is essential for development and functional integrity of the subthalamic nucleus, in Scientific Reports, 6(1), 38611-38611.

Associated projects

Number Title Start Funding scheme
160317 Role of Foxa1 in central regulation of physical activity and sexual maturation 01.04.2015 Project funding (Div. I-III)
160317 Role of Foxa1 in central regulation of physical activity and sexual maturation 01.04.2015 Project funding (Div. I-III)

Abstract

Regulation and function of forkhead transcription factors A1 and A2 in metabolismThe forkhead transcription factors of subfamily A (FoxA1-3) display a remarkable functional diversity and are involved in a wide variety of biological processes including development and metabolism. FoxA1 and A2 fulfill important and partially overlapping roles in metabolism by associating remodeling chromatin and transcriptional control of gene expression in liver, pancreatic islets and the hypothalamus. Previous studies in our laboratory have shown that FoxA2 activity is regulated by insulin signaling which leads to phosphorylation at theonine156, functional inactivation and nuclear exclusion. FoxA2 is a mediator of the fasting/feeding response through transcriptional regulation of genes involved in fatty acid oxidation and ketone body formation in the liver and control of orexin and melanin-concentrating hormone (MCH) in the hypothalamus. Remarkably, FoxA2 is permanently inactivated in these organs in hyperinsulinemic insulin resistant and obesity states, thereby contributing to the development of hepatic steatosis and reducing the motivation for spontaneous physical inactivity. In this application we hypothesize (and present first preliminary data) that other posttranslational modifications (i.e. phosphorylation, acetylation and methylation) also contribute to the complex regulation of FoxA proteins and propose to systematically study their physiological role during metabolic stress and in pathological conditions such as insulin resistance, diabetes and obesity. The proposed studies include four specific aims:In Aim 1 we will perform a detailed biochemical characterization of our recently identified posttranslational modifications in FoxA1 and FoxA2. We will investigate upstream signalling pathways and identify the enzymes responsible for the respective posttranslational modifications (PTMs) and their regulation. In addition we will study the role of the PMTs in modulating the transcriptional activity, DNA binding, cofactor recruitment, cellular localization and protein stability of FoxA1/2 proteins.In Aim 2 we will investigate the role of specific Foxa2-PTMs in pancreatic b-cells, liver, and hypothalamus in vivo by characterizing knock-in mice harboring conditional phosphorylation- and acetylation-deficient and -mimic FoxA2 mutations and study their role in physiological and metabolic disease states.In Aim 3 we will elucidate the effect of Foxa2 activity on longevity. FoxA2 is a downstream target of insulin signaling and acetylase/deacetylase signaling pathways. We hypothesize that Foxa2 also mediates the extended lifespan, a phenotype that has been observed in mutant mice and other model systems with decreased insulin signaling. To this end we will measure lifespan and metabolic profiles in mice harboring conditional and specific activating and inactivating phosphorylation and acetylation mutants in the liver and brain. In Aim 4 we will study the specific role of FoxA1 in the lateral hypothalamus. Genetic studies in conditional FoxA1 mutant mice indicate that lack of FoxA1 expression in the CNS is responsible for the feeding defect in newborn mice leading to early postnatal mortality. To study the role of FoxA1 in the adult brain we will ablate FoxA1 in specific regions of the brain and study the physiological effects on metabolic control, eating behavior and physical activity. Furthermore, we will identify and characterize the relevant targets of FoxA1 by gene expression analysis and biochemical analysis of putative promoters. Together, the expected results of the proposed research will shed light on i.) the molecular mechanisms by which FoxA1/2 factors are regulated in response to environmental and intracellular signals, ii) their role in the physiological control of metabolism, during metabolic stress and in disease, iii) the role of specific PTMs in regulating life span and iv) the role of FoxA1 in the central regulation of metabolism and spontaneous physical activity.
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