|
1
|
Chen Y, Anderson MT, Payne N, Santori FR, Ivanova NB. Nuclear Receptors and the Hidden Language of the Metabolome. Cells 2024; 13:1284. [PMID: 39120315 PMCID: PMC11311682 DOI: 10.3390/cells13151284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome.
Collapse
Affiliation(s)
- Yujie Chen
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - Matthew Tom Anderson
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Nathaniel Payne
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Fabio R. Santori
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Natalia B. Ivanova
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| |
Collapse
|
|
2
|
Ferreira LGA, Kizys MML, Gama GAC, Pachernegg S, Robevska G, Sinclair AH, Ayers KL, Dias-da-Silva MR. COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors. Cell Biosci 2024; 14:3. [PMID: 38178246 PMCID: PMC10768475 DOI: 10.1186/s13578-023-01182-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/02/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. RESULTS By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. CONCLUSIONS Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency.
Collapse
Affiliation(s)
- Lucas G A Ferreira
- Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Murdoch Children's Research Institute, Melbourne, Australia
| | - Marina M L Kizys
- Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Gabriel A C Gama
- Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Svenja Pachernegg
- Murdoch Children's Research Institute, Melbourne, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | | | - Andrew H Sinclair
- Murdoch Children's Research Institute, Melbourne, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | - Katie L Ayers
- Murdoch Children's Research Institute, Melbourne, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | - Magnus R Dias-da-Silva
- Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
| |
Collapse
|
|
3
|
Rzasa P, Whelan S, Farahmand P, Cai H, Guterman I, Palacios-Gallego R, Undru SS, Sandford L, Green C, Andreadi C, Mintseva M, Parrott E, Jin H, Hey F, Giblett S, Sylvius NB, Allcock NS, Straatman-Iwanowska A, Feuda R, Tufarelli C, Brown K, Pritchard C, Rufini A. BRAF V600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism. Commun Biol 2023; 6:962. [PMID: 37735514 PMCID: PMC10514332 DOI: 10.1038/s42003-023-05331-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023] Open
Abstract
BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
Collapse
Affiliation(s)
- Paulina Rzasa
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Sarah Whelan
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Pooyeh Farahmand
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Hong Cai
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Inna Guterman
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | | | - Shanthi S Undru
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Lauren Sandford
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Caleb Green
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Catherine Andreadi
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Maria Mintseva
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy
| | - Emma Parrott
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Hong Jin
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Fiona Hey
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Susan Giblett
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Nicolas B Sylvius
- NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK
| | - Natalie S Allcock
- University of Leicester Core Biotechnology Services Electron Microscopy Facility, Leicester, UK
| | | | - Roberto Feuda
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - Cristina Tufarelli
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Karen Brown
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Catrin Pritchard
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Alessandro Rufini
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
- Dipartimento di Bioscienze, University of Milan, Milan, Italy.
| |
Collapse
|
|
4
|
Iyer DR, Venkatraman J, Tanguy E, Vitale N, Mahapatra NR. Chromogranin A and its derived peptides: potential regulators of cholesterol homeostasis. Cell Mol Life Sci 2023; 80:271. [PMID: 37642733 PMCID: PMC11072126 DOI: 10.1007/s00018-023-04908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/31/2023]
Abstract
Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.
Collapse
Affiliation(s)
- Dhanya R Iyer
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Janani Venkatraman
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Emeline Tanguy
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France
| | - Nicolas Vitale
- Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212 and Université de Strasbourg, 5 Rue Blaise Pascal, 67000, Strasbourg, France.
| | - Nitish R Mahapatra
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, 600036, India.
| |
Collapse
|
|
5
|
Davalos V, Lovell CD, Von Itter R, Dolgalev I, Agrawal P, Baptiste G, Kahler DJ, Sokolova E, Moran S, Piqué L, Vega-Saenz de Miera E, Fontanals-Cirera B, Karz A, Tsirigos A, Yun C, Darvishian F, Etchevers HC, Osman I, Esteller M, Schober M, Hernando E. An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma. Nat Commun 2023; 14:1867. [PMID: 37015919 PMCID: PMC10073109 DOI: 10.1038/s41467-023-36967-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/24/2023] [Indexed: 04/06/2023] Open
Abstract
Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 - isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
Collapse
Affiliation(s)
- Veronica Davalos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
| | - Claudia D Lovell
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - Richard Von Itter
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - Igor Dolgalev
- Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Praveen Agrawal
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
- Department of Molecular Pharmacology, Albert Einstein College of Medicine/ Montefiore, Bronx, NY, 10461, USA
| | - Gillian Baptiste
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - David J Kahler
- High Throughput Biology Core, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Elena Sokolova
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - Sebastian Moran
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
| | - Laia Piqué
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
| | - Eleazar Vega-Saenz de Miera
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
- The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Barbara Fontanals-Cirera
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - Alcida Karz
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | - Aristotelis Tsirigos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Chi Yun
- High Throughput Biology Core, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Farbod Darvishian
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
| | | | - Iman Osman
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA
- The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Manel Esteller
- Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
- Centro de Investigacion Biomedica en Red, Cancer (CIBERONC), Madrid, Spain
| | - Markus Schober
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.
- The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA.
- Department of Cell Biology, New York Grossman University School of Medicine, New York, NY, 10016, USA.
| | - Eva Hernando
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.
- Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.
| |
Collapse
|
|
6
|
Polvani S, Pepe S, Tempesti S, Tarocchi M, Marroncini G, Bencini L, Ceni E, Mello T, Picariello L, Simeone I, Grappone C, Dragoni G, Antonuzzo L, Giommoni E, Milani S, Galli A. Isoforms of the orphan nuclear receptor COUP‑TFII differentially modulate pancreatic cancer progression. Int J Oncol 2022; 60:55. [PMID: 35348189 PMCID: PMC8997336 DOI: 10.3892/ijo.2022.5345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/07/2022] [Indexed: 12/24/2022] Open
Abstract
The expression of the nuclear receptor transcription factor (TF) COUP-TFII is broadly associated with cell differentiation and cancer development, including of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with one of the poorest prognoses among cancers worldwide. Recent studies have started to investigate the pathological and physiological roles of a novel COUP-TFII isoform (COUP-TFII_V2) that lacks the DNA-binding domain. As the role of the canonical COUP-TFII in PDAC was previously demonstrated, the present study evaluated whether COUP-TFII_V2 may have a functional role in PDAC. It was demonstrated that COUP-TFII_V2 naturally occurs in PDAC cells and in primary samples, where its expression is consistent with shorter overall survival and peripheral invasion. Of note, COUP-TFII_V2, exhibiting nuclear and cytosolic expression, is linked to epithelial to mesenchymal transition (EMT) and cancer progression, as confirmed by nude mouse experiments. The present results demonstrated that COUP-TFII_V2 distinctively regulates the EMT of PDAC and, similarly to its sibling, it is associated with tumor aggressiveness. The two isoforms have both overlapping and exclusive functions that cooperate with cancer growth and dissemination. By studying how PDAC cells switch from one isoform to the other, novel insight into cancer biology was gained, indicating that this receptor may serve as a novel possible target for PDAC management.
Collapse
Affiliation(s)
- Simone Polvani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Sara Pepe
- Core Research Laboratory, Institute for Cancer Research and Prevention, I-50139 Florence, Italy
| | - Sara Tempesti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Mirko Tarocchi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Giada Marroncini
- Endocrinology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50139 Florence, Italy
| | - Lapo Bencini
- Oncology General Surgery, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Elisabetta Ceni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Tommaso Mello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Lucia Picariello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Irene Simeone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Cecilia Grappone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, I-50139 Florence, Italy
| | - Elisa Giommoni
- Medical Oncology, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, I-50134 Florence, Italy
| |
Collapse
|
|
7
|
Wijesena HR, Kachman SD, Lents CA, Riethoven JJ, Trenhaile-Grannemann MD, Safranski TJ, Spangler ML, Ciobanu DC. Fine mapping genetic variants associated with age at puberty and sow fertility using SowPro90 genotyping array. J Anim Sci 2021; 98:5901653. [PMID: 32888012 DOI: 10.1093/jas/skaa293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/01/2020] [Indexed: 12/30/2022] Open
Abstract
Sow fertility traits, such as litter size and the number of lifetime parities produced (reproductive longevity), are economically important. Selection for these traits is difficult because they are lowly heritable and expressed late in life. Age at puberty (AP) is an early indicator of reproductive longevity. Here, we utilized a custom Affymetrix single-nucleotide polymorphisms (SNPs) array (SowPro90) enriched with positional candidate genetic variants for AP and a haplotype-based genome-wide association study to fine map the genetic sources associated with AP and other fertility traits in research (University of Nebraska-Lincoln [UNL]) and commercial sow populations. Five major quantitative trait loci (QTL) located on four Sus scrofa chromosomes (SSC2, SSC7, SSC14, and SSC18) were discovered for AP in the UNL population. Negative correlations (r = -0.96 to -0.10; P < 0.0001) were observed at each QTL between genomic estimated breeding values for AP and reproductive longevity measured as lifetime number of parities (LTNP). Some of the SNPs discovered in the major QTL regions for AP were located in candidate genes with fertility-associated gene ontologies (e.g., P2RX3, NR2F2, OAS1, and PTPN11). These SNPs showed significant (P < 0.05) or suggestive (P < 0.15) associations with AP, reproductive longevity, and litter size traits in the UNL population and litter size traits in the commercial sows. For example, in the UNL population, when the number of favorable alleles of an SNP located in the 3' untranslated region of PTPN11 (SSC14) increased, AP decreased (P < 0.0001), while LTNP increased (P < 0.10). Additionally, a suggestive difference in the observed NR2F2 isoforms usage was hypothesized to be the source of the QTL for puberty onset mapped on SSC7. It will be beneficial to further characterize these candidate SNPs and genes to understand their impact on protein sequence and function, gene expression, splicing process, and how these changes affect the phenotypic variation of fertility traits.
Collapse
Affiliation(s)
- Hiruni R Wijesena
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE
| | - Stephen D Kachman
- Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE
| | - Clay A Lents
- U.S. Meat Animal Research Center, USDA, ARS, Clay Center, NE
| | | | | | - Tim J Safranski
- Department of Animal Sciences, University of Missouri, Columbia, MO
| | - Matthew L Spangler
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE
| | - Daniel C Ciobanu
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE
| |
Collapse
|
|
8
|
Polvani S, Pepe S, Milani S, Galli A. COUP-TFII in Health and Disease. Cells 2019; 9:E101. [PMID: 31906104 PMCID: PMC7016888 DOI: 10.3390/cells9010101] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/27/2019] [Accepted: 12/29/2019] [Indexed: 12/14/2022] Open
Abstract
The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR.
Collapse
Affiliation(s)
- Simone Polvani
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Gastroenterology Unit, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy; (S.P.); (S.M.)
- Department of Experimental and Clinical Medicine, University of Florence, largo Brambilla 50, 50139 Firenze, Italy
| | - Sara Pepe
- Istituto per la Ricerca, la Prevenzione e la rete Oncologica (ISPRO), viale Pieraccini 6, 50139 Firenze, Italy;
- Department of Medical Biotechnologies, University of Siena, via M. Bracci 16, 53100 Siena, Italy
| | - Stefano Milani
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Gastroenterology Unit, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy; (S.P.); (S.M.)
| | - Andrea Galli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Gastroenterology Unit, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy; (S.P.); (S.M.)
| |
Collapse
|
|
9
|
Wang J, Abhinav P, Xu YJ, Li RG, Zhang M, Qiu XB, Di RM, Qiao Q, Li XM, Huang RT, Xue S, Yang YQ. NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve. Int J Mol Med 2019; 43:1839-1846. [PMID: 30720060 DOI: 10.3892/ijmm.2019.4087] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 01/22/2019] [Indexed: 11/06/2022] Open
Abstract
Congenital bicuspid aortic valve (BAV) represents the most common type of cardiac birth defect affecting 0.4‑2% of the general population, and accounts for a markedly increased incidence of life‑threatening complications, including valvulopathy and aortopathy. Accumulating evidence has demonstrated the genetic basis of BAV. However, the genetic basis for BAV in the majority of cases remains to be elucidated. In the present study, the coding regions and splicing donors/acceptors of the nuclear receptor subfamily 2 group F member 2 (NR2F2) gene, which encodes a transcription factor essential for proper cardiovascular development, were sequenced in 176 unrelated cases of congenital BAV. The available family members of the proband carrying an identified NR2F2 mutation and 280 unrelated, sex‑ and ethnicity‑matched healthy individuals as controls were additionally genotyped for NR2F2. The functional effect of the mutation was characterized using a dual‑luciferase reporter assay system. As a result, a novel heterozygous NR2F2 mutation, NM_021005.3: c.288C>A; p.(Cys96*), was identified in a family with BAV, which was transmitted in an autosomal dominant mode with complete penetrance. The nonsense mutation was absent from the 560 control chromosomes. Functional analysis identified that the mutant NR2F2 protein had no transcriptional activity. Furthermore, the mutation disrupted the synergistic transcriptional activation between NR2F2 and transcription factor GATA‑4, another transcription factor that is associated with BAV. These findings suggested NR2F2 as a novel susceptibility gene of human BAV, which reveals a novel molecular pathogenesis underpinning BAV.
Collapse
Affiliation(s)
- Juan Wang
- Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Pradhan Abhinav
- Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
| | - Ying-Jia Xu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Ruo-Gu Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Min Zhang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Xing-Biao Qiu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Ruo-Min Di
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Qi Qiao
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Xiu-Mei Li
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| | - Ri-Tai Huang
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Song Xue
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
| | - Yi-Qing Yang
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China
| |
Collapse
|
|
10
|
Ashraf UM, Sanchez ER, Kumarasamy S. COUP-TFII revisited: Its role in metabolic gene regulation. Steroids 2019; 141:63-69. [PMID: 30481528 PMCID: PMC6435262 DOI: 10.1016/j.steroids.2018.11.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/10/2018] [Accepted: 11/23/2018] [Indexed: 02/07/2023]
Abstract
Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) is an orphan member of the nuclear receptor family of transcriptional regulators. Although hormonal activation of COUP-TFII has not yet been identified, rodent genetic models have uncovered vital and diverse roles for COUP-TFII in biological processes. These include control of cardiac function and angiogenesis, reproduction, neuronal development, cell fate and organogenesis. Recently, an emerging body of evidence has demonstrated COUP-TFII involvement in various metabolic systems such as adipogenesis, lipid metabolism, hepatic gluconeogenesis, insulin secretion, and regulation of blood pressure. The potential relevance of these observations to human pathology has been corroborated by the identification of single nucleotide polymorphism in the human COUP-TFII promoter controlling insulin sensitivity. Of particular interest to metabolism is the ability of COUP-TFII to interact with the Glucocorticoid Receptor (GR). This interaction is known to control gluconeogenesis, principally through direct binding of COUP-TFII/GR complexes to the promoters of gluconeogenic enzyme genes. However, it is likely that this interaction is critical to other metabolic processes, since GR, like COUP-TFII, is an essential regulator of adipogenesis, insulin sensitivity, and blood pressure. This review will highlight these unique roles of COUP-TFII in metabolic gene regulation.
Collapse
Affiliation(s)
- Usman M Ashraf
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Edwin R Sanchez
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA; Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Sivarajan Kumarasamy
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA; Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
| |
Collapse
|
|
11
|
Qiao XH, Wang Q, Wang J, Liu XY, Xu YJ, Huang RT, Xue S, Li YJ, Zhang M, Qu XK, Li RG, Qiu XB, Yang YQ. A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect. Eur J Med Genet 2017; 61:197-203. [PMID: 29222010 DOI: 10.1016/j.ejmg.2017.12.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 11/06/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023]
Abstract
Congenital heart defect (CHD) is the most common type of birth defect in humans and a leading cause of infant morbidity and mortality. Previous studies have demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, the genetic basis of CHD remains poorly understood due to substantial genetic heterogeneity. In this study, the coding exons and splicing boundaries of the NR2F2 gene, which encodes a pleiotropic transcription factor required for normal cardiovascular development, were sequenced in 168 unrelated patients with CHD, and a novel mutation (c.247G > T, equivalent to p.G83X) was detected in a patient with double outlet right ventricle as well as ventricular septal defect. Genetic scanning of the mutation carrier's relatives available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the index patient's pedigree displayed that the mutation co-segregated with CHD, which was transmitted as an autosomal dominant trait with complete penetrance. The nonsense mutation was absent in 230 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system revealed that the mutant NR2F2 protein had no transcriptional activity as compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD. This study firstly associates NR2F2 loss-of-function mutation with an increased susceptibility to double outlet right ventricle in humans, which provides further significant insight into the molecular mechanisms underpinning CHD, suggesting potential implications for genetic counseling of CHD families and personalized treatment of CHD patients.
Collapse
Affiliation(s)
- Xiao-Hui Qiao
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qian Wang
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Juan Wang
- Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xing-Yuan Liu
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Ying-Jia Xu
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Ri-Tai Huang
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Song Xue
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan-Jie Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Min Zhang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xin-Kai Qu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruo-Gu Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xing-Biao Qiu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yi-Qing Yang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
12
|
Schwach V, Verkerk AO, Mol M, Monshouwer-Kloots JJ, Devalla HD, Orlova VV, Anastassiadis K, Mummery CL, Davis RP, Passier R. A COUP-TFII Human Embryonic Stem Cell Reporter Line to Identify and Select Atrial Cardiomyocytes. Stem Cell Reports 2017; 9:1765-1779. [PMID: 29173897 PMCID: PMC5785710 DOI: 10.1016/j.stemcr.2017.10.024] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 10/26/2017] [Accepted: 10/27/2017] [Indexed: 02/04/2023] Open
Abstract
Reporter cell lines have already proven valuable in identifying, tracking, and purifying cardiac subtypes and progenitors during differentiation of human pluripotent stem cells (hPSCs). We previously showed that chick ovalbumin upstream promoter transcription factor II (COUP-TFII) is highly enriched in human atrial cardiomyocytes (CMs), but not ventricular. Here, we targeted mCherry to the COUP-TFII genomic locus in hPSCs expressing GFP from the NKX2.5 locus. This dual atrial NKX2.5EGFP/+-COUP-TFIImCherry/+ reporter line allowed identification and selection of GFP+ (G+)/mCherry+ (M+) CMs following cardiac differentiation. These cells exhibited transcriptional and functional properties of atrial CMs, whereas G+/M− CMs displayed ventricular characteristics. Via CRISPR/Cas9-mediated knockout, we demonstrated that COUP-TFII is not required for atrial specification in hPSCs. This new tool allowed selection of human atrial and ventricular CMs from mixed populations, of relevance for studying cardiac specification, developing human atrial disease models, and examining distinct effects of drugs on the atrium versus ventricle.
Dual NKX2.5EGFP/+-COUP-TFIImCherry/+ hPSCs to identify atrial cardiomyocytes COUP-TFII is not required for atrial specification of hPSCs in vitro
Collapse
Affiliation(s)
- Verena Schwach
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Arie O Verkerk
- Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Mervyn Mol
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Harsha D Devalla
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Valeria V Orlova
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Richard P Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Robert Passier
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands; Department of Applied Stem Cell Technologies, MIRA Institute, University of Twente, Twente, the Netherlands.
| |
Collapse
|
|
13
|
Planchais J, Boutant M, Fauveau V, Qing LD, Sabra-Makke L, Bossard P, Vasseur-Cognet M, Pégorier JP. The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice. Am J Physiol Endocrinol Metab 2015; 308:E868-78. [PMID: 25783893 DOI: 10.1152/ajpendo.00433.2014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 03/12/2015] [Indexed: 01/08/2023]
Abstract
Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARα. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII-DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARα target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival.
Collapse
Affiliation(s)
- Julien Planchais
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Marie Boutant
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Véronique Fauveau
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Lou Dan Qing
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and Laboratoires Fabre, Boulogne Cedex, France
| | - Lina Sabra-Makke
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Pascale Bossard
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Mireille Vasseur-Cognet
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| | - Jean-Paul Pégorier
- Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France; and
| |
Collapse
|
|
14
|
Polvani S, Tarocchi M, Tempesti S, Galli A. Nuclear receptors and pathogenesis of pancreatic cancer. World J Gastroenterol 2014; 20:12062-12081. [PMID: 25232244 PMCID: PMC4161795 DOI: 10.3748/wjg.v20.i34.12062] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
Collapse
|
|
15
|
Bao Y, Gu D, Feng W, Sun X, Wang X, Zhang X, Shi Q, Cui G, Yu H, Tang C, Deng A. COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1. Br J Cancer 2014; 111:933-43. [PMID: 25032732 PMCID: PMC4150277 DOI: 10.1038/bjc.2014.373] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/26/2014] [Accepted: 05/29/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, also known as NR2F2) promotes metastasis by functioning in the tumour microenvironment; however, the role of COUP-TFII in colorectal cancer remains unknown. METHODS Human colon adenocarcinoma tissues were collected to test COUP-TFII expression. Wound-healing and cell invasion assay were used to evaluate migration and invasion of cells. Chicken ovalbumin upstream promoter-transcription factor II and related protein expression was assessed by immunostaining, immunoblotting and real-time PCR assay. Tamoxifen-inducible COUP-TFII knockout mice were employed to test COUP-TFII functions on colon cancer metastasis in vivo. RESULTS Elevated expression of COUP-TFII in colorectal adenocarcinoma tissue correlated with overexpression of the Snail1 transcription factor. High COUP-TFII expression correlated with metastasis and shorter patient survival. Chicken ovalbumin upstream promoter-transcription factor II regulated the migration and invasion of cancer cells. With Snail1, COUP-TFII inhibited expression of adherence molecules such as ZO-1, E-cadherin and β-catenin in colorectal cancer cells. Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo. Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes. CONCLUSIONS Chicken ovalbumin upstream promoter-transcription factor II was crucial for colorectal cancer metastasis and regulated cell migration and metastasis in conjunction with Snail1. Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.
Collapse
Affiliation(s)
- Y Bao
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - D Gu
- Huzhou Central Hospital, Huzhou 313000, China
| | - W Feng
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - X Sun
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - X Wang
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - X Zhang
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - Q Shi
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - G Cui
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - H Yu
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - C Tang
- First Affiliated Hospital, Huzhou Teachers College, the First People's Hospital of Huzhou, Huzhou 313000, China
| | - A Deng
- Department of Laboratory Diagnostic, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| |
Collapse
|