Publications by authors named "Remi Houlgatte"

67 Publications

Characteristics Of Lymphoma In Patients With Inflammatory Bowel Disease: A Systematic Review.

J Crohns Colitis 2020 Sep 19. Epub 2020 Sep 19.

Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France.

Introduction: Lymphoma is a dreaded complication of inflammatory bowel diseases (IBD). Knowledge about lymphoma in patients with IBD is limited to epidemiological data and risk factors description. We performed a systematic review to describe clinical characteristics and prognosis of lymphoma in patients with IBD.

Methods: Electronic databases were searched up to 1 st June 2020. All published clinical characteristics of lymphoma occurring in patients with IBD were collected.

Results: Eleven studies were included. A total of 589 lymphomas were described in patients with IBD. As seen in de novo lymphoma, non-Hodgkin's lymphoma (NHL) was the most common histological subtype (83.9%). Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma were the most represented NHL in patients with IBD (30% and 13% respectively). Two main differences were observed in comparison to de novo lymphoma: primary intestinal lymphoma (PIL) represented a large part of lymphoma in patients with IBD (22% to 75%) whereas mucosa-associated lymphoid tissue (MALT) lymphoma was under-represented. Epstein-Barr virus (EBV) positive status was observed in a large part of tumors (44 to 75%). Survival data of lymphoma in patients with IBD were similar to that of de novo lymphoma.

Discussion: This systematic review first highlights that PIL (especially DLBCL subtype) is significantly more frequent in patients with IBD and represents the most common entity. Conversely, MALT lymphoma is extremely rare in IBD population. However, the overall quality of the evidence is low. Further studies are required to better define lymphoma characteristics in patients with IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa193DOI Listing
September 2020

Genomic and molecular alterations in human inflammatory bowel disease-associated colorectal cancer.

United European Gastroenterol J 2020 07 8;8(6):675-684. Epub 2020 Apr 8.

Department of Gastroenterology, Nancy University Hospital, University of Lorraine, France.

Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFβ pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.
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http://dx.doi.org/10.1177/2050640620919254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437079PMC
July 2020

Ki-67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1-mutant and 1p/19q-codeleted: a multicenter study from the French POLA network.

Brain Pathol 2020 05 10;30(3):465-478. Epub 2019 Oct 10.

Department of Pathology, CHRU, Nancy, France.

Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype.
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http://dx.doi.org/10.1111/bpa.12788DOI Listing
May 2020

Encapsulation of S-nitrosoglutathione: a transcriptomic validation.

Drug Dev Ind Pharm 2019 Mar 6;45(3):423-429. Epub 2018 Dec 6.

a EA 3452 CITHÉFOR , Université de Lorraine, Faculté de Pharmacie , Nancy , France.

Objective: S-nitrosogluthatione (GSNO), a S-nitrosothiol, is a commonly used as nitric oxide (NO) donor. However, its half-life is too short for a direct therapeutic use. To protect and ensure a sustained release of NO, the encapsulation of GSNO into nanoparticles may be an interesting option.

Methods: In this work, we have investigated the early (4 h) and late (24 h) transcriptomic response of THP-1 human monocytes cells to two doses (1.4 and 6 µM) of either free or Eudragit nano-encapsulated GSNO using RNA microarray.

Results: After exposure to free GSNO, genes mainly involved in apoptosis, cell differentiation, immune response and metabolic processes were differentially expressed. Although, cells exposed to free or encapsulated GSNO behave differently, activation of genes involved in blood coagulation, immune response and cell cycle was observed in both conditions.

Conclusions: These results suggest that the encapsulation of low doses of GSNO into Eudragit nanoparticles leads to a progressive release of GSNO making this compound a possible oral therapy for several biomedical applications like inflammatory bowel diseases.
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http://dx.doi.org/10.1080/03639045.2018.1546313DOI Listing
March 2019

Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR.

Nucleic Acids Res 2018 09;46(15):7844-7857

INSERM UMRS 954 NGERE - Nutrition, Genetics, and Environmental Risk Exposure and National Center of Inborn Errors of Metabolism, Faculty of Medicine of Nancy, University of Lorraine and University Regional Hospital Center of Nancy, Vandoeuvre-lès-Nancy, F-54000, France.

The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.
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http://dx.doi.org/10.1093/nar/gky634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125644PMC
September 2018

Transcriptional orchestration of mitochondrial homeostasis in a cellular model of PGC-1-related coactivator-dependent thyroid tumor.

Oncotarget 2018 Mar 23;9(22):15883-15894. Epub 2018 Mar 23.

Inserm UMR 1048, I2MC, 31432 TOULOUSE Cedex 4, France.

The PGC-1 (Peroxisome proliferator-activated receptor Gamma Coactivator-1) family of coactivators (PGC-1α, PGC-1β, and PRC) plays a central role in the transcriptional control of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) processes. These coactivators integrate mitochondrial energy production into cell metabolism using complementary pathways. The XTC.UC1 cell line is a mitochondria-rich model of thyroid tumors whose biogenesis is almost exclusively dependent on PRC. Here we aim to propose an integrative view of the cellular pathways regulated by PRC through integration of cDNA and miRNA microarray data and chromatin immunoprecipitation results obtained from XTC.UC1 cells invalidated for PRC. This study showes that PRC induces a complex network of cellular functions interacting with at least one to five of the studied transcription factors (Estrogen Related Receptor alpha, ERR1; Nuclear-Respiratory Factors, NRF1 and NRF2; cAMP Response Element Binding, CREB; and Ying Yang, YY1). Our data confirm that ERR1 is a key partner of PRC in the regulation of mitochondrial functions and suggest a potential role of this complex in RNA processing. PRC is also involved in transcriptional regulatory complexes targeting 12 miRNAs, five of which are involved in the control of the OXPHOS process. Our findings demonstrate that the PRC coactivator can act in complex with several transcription factors and regulate miRNA expression to control the fine regulation of main metabolic functions in the cell. Therefore, in PGC-1α/β-associated pathologies, PRC, as a metabolic sensor, may ensure mitochondrial homeostasis.
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http://dx.doi.org/10.18632/oncotarget.24633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882305PMC
March 2018

Identification of genomic differences among peripheral arterial beds in atherosclerotic and healthy arteries.

Sci Rep 2018 03 2;8(1):3940. Epub 2018 Mar 2.

UMR1238 INSERM, Université de Nantes, CHU de Nantes, Nantes, France.

Calcification is independently associated with cardiovascular events and morbidity. The calcification burden in atherosclerotic lesions quantitatively and qualitatively differs between arterial beds. Cardiovascular risk factors (CVRF) differentially affect plaque development between arterial beds. The aim of this study was to evaluate the impact of CVRF on atherosclerotic plaque calcification and to further study the molecular arterial heterogeneity that could account for these differences. Histological analysis was performed on atherosclerotic plaques from 153 carotid, 97 femoral and 28 infrapopliteal arteries. CVRF showed minor associations with plaque calcification: age and hypertension affected only the overall presence of calcification but not the type of the calcification, which significantly differed between arterial beds. Transcriptome analysis revealed distinct gene expression profiles associated with each territory in atherosclerotic and healthy arteries. Canonical pathway analysis showed the preferential involvement of immune system-related processes in both atherosclerotic and healthy carotid arteries. Bone development-related genes were among those mostly enriched in atherosclerotic and healthy femoral arteries, which are more prone to developing endochondral calcification. This study highlights the heterogeneous nature of arteries from different peripheral vascular beds and contributes to a better understanding of atherosclerosis formation and evolution.
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http://dx.doi.org/10.1038/s41598-018-22292-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834518PMC
March 2018

Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification.

PLoS One 2018 26;13(1):e0191976. Epub 2018 Jan 26.

INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France.

Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcification among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ signaling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786328PMC
March 2018

VEGF, is predictor for survival in activated B-cell-like diffuse large B-cell lymphoma and is related to an immune response gene signature conserved in cancers.

Oncotarget 2017 Oct 19;8(53):90808-90824. Epub 2017 Jul 19.

Paris Diderot University, Sorbonne Paris Cité, Paris, France.

Tumor microenvironment including endothelial and immune cells plays a crucial role in tumor progression and has been shown to dramatically influence cancer survival. In this study, we investigated the clinical relevance of the gene expression of key mediators of angiogenesis, VEGF isoforms 121, 165, and 189, and their receptors (VEGFR-1 and R-2) in a cohort of patients ( = 37) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL). In patients with ABC-like DLBCL, but not in patients with GCB-like DLBCL, low expression was associated with a significantly better survival than in those with high level: 4-year overall survival at 100% vs 36% ( = .011), respectively. A specific gene signature including 57 genes was correlated to expression level and was analyzed using a discovery process in 1,842 GSE datasets of public microarray studies. This gene signature was significantly expressed in other cancer datasets and was associated with immune response. In conclusion, low expression level was significantly associated with a good prognosis in relapsed/refractory ABC-like DLBCL, and with a well-conserved gene-expression profiling signature related to immune response. These findings pave the way for rationalization of drugs targeting immune response in refractory/relapsed ABC-like DLBCL.
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http://dx.doi.org/10.18632/oncotarget.19385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710886PMC
October 2017

Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia.

J Pathol 2017 08 5;242(4):421-434. Epub 2017 Jul 5.

INSERM U954, Faculty of Medicine, Université de Lorraine, Vandoeuvre-lès-Nancy, France.

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10 ) and IOMM-Lee (p = 4 × 10 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4916DOI Listing
August 2017

A composite score associated with spontaneous operational tolerance in kidney transplant recipients.

Kidney Int 2017 06 24;91(6):1473-1481. Epub 2017 Feb 24.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; CIC Biotherapy, CHU Nantes, Nantes, France. Electronic address:

New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplant recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94-1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy.
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http://dx.doi.org/10.1016/j.kint.2016.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432017PMC
June 2017

Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet.

Sci Rep 2016 11 17;6:37207. Epub 2016 Nov 17.

Inserm U954, Nutrition-Genetics-Environmental Risk Exposure (N-GERE), University of Lorraine, BP 184, 54511, Vandœuvre-lès-Nancy, France.

Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet.
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http://dx.doi.org/10.1038/srep37207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112564PMC
November 2016

Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses.

Oncotarget 2016 Dec;7(51):83987-84002

Inserm U954, Faculty of Medicine, Nancy, France.

Despite major advances in first-line treatment, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will experience treatment failure. Prognosis is particularly poor for relapses occurring less than one year after the end of first-line treatment (early relapses/ER) compared to those occurring more than one year after (late relapses/LR). To better understand genomic alterations underlying the delay of relapse, we identified copy number variations (CNVs) on 39 tumor samples from a homogeneous series of patients included in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) prospective study. To identify CNVs associated with ER or LR, we devised an original method based on Significance Analysis of Microarrays, a permutation-based method which allows control of false positives due to multiple testing. Deletions of CDKN2A/B (28%) and IBTK (23%) were frequent events in relapsed DLBCLs. We identified 56 protein-coding genes and 25 long non-coding RNAs with significantly differential CNVs distribution between ER and LR DLBCLs, with a false discovery rate < 0.05. In ER DLBCLs, CNVs were related to transcription regulation, cell cycle and apoptosis, with duplications of histone H1T (31%), deletions of DIABLO (26%), PTMS (21%) and CK2B (15%). In LR DLBCLs, CNVs were related to immune response, with deletions of B2M (20%) and CD58 (10%), cell proliferation regulation, with duplications of HES1 (25%) and DVL3 (20%), and transcription regulation, with MTERF4 deletions (20%). This study provides new insights into the genetic aberrations in relapsed DLBCLs and suggest pathway-targeted therapies in ER and LR DLBCLs.
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http://dx.doi.org/10.18632/oncotarget.9793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356640PMC
December 2016

Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency.

FASEB J 2016 06 18;30(6):2382-99. Epub 2016 Mar 18.

Centre de Neurophysique, Physiologie et Pathologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8119, Université Paris Descartes, Sorbonne Paris Cité, Paris France;

The collagen ColQ anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction (NMJ). It also binds MuSK and perlecan/dystroglycan, 2 signaling platforms of the postsynaptic domain. Mutations in ColQ cause a congenital myasthenic syndrome (CMS) with AChE deficiency. Because the absence of AChE does not fully explain the complexity of the syndrome and there is no curative treatment for the disease, we explored additional potential targets of ColQ by conducting a large genetic screening of ColQ-deficient mice, a model for CMS with AChE deficiency, and analyzed their NMJ and muscle phenotypes. We demonstrated that ColQ controls the development and the maturation of the postsynaptic domain by regulating synaptic gene expression. Notably, ColQ deficiency leads to an up-regulation of the 5 subunits of the nicotinic acetylcholine receptor (AChR), leading to mixed mature and immature AChRs at the NMJ of adult mice. ColQ also regulates the expression of extracellular matrix (ECM) components. However, whereas the ECM mRNAs were down-regulated in vitro, compensation seemed to occur in vivo to maintain normal levels of these mRNAs. Finally, ColQ deficiency leads to a general atrophic phenotype and hypoplasia that affect fast muscles. This study points to new specific hallmarks for this CMS.-Sigoillot, S. M., Bourgeois, F., Karmouch, J., Molgó, J., Dobbertin, A., Chevalier, C., Houlgatte, R., Léger, J., Legay, C. Neuromuscular junction immaturity and muscle atrophy are hallmarks of the ColQ-deficient mouse, a model of congenital myasthenic syndrome with acetylcholinesterase deficiency.
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http://dx.doi.org/10.1096/fj.201500162DOI Listing
June 2016

A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft.

Kidney Int 2015 May 28;87(5):984-95. Epub 2015 Jan 28.

1] INSERM, UMR 1064, Nantes, France [2] CHU de Nantes, ITUN, Nantes, France [3] Université de Nantes, Faculté de Médecine, Nantes, France.

Patients tolerant to a kidney graft display a specific blood cell transcriptional pattern but results from five different studies were inconsistent, raising the question of relevance for future clinical application. To resolve this, we sought to identify a common gene signature, specific functional and cellular components, and discriminating biomarkers for tolerance following kidney transplantation. A meta-analysis of studies identified a robust gene signature involving proliferation of B and CD4 T cells, and inhibition of CD14 monocyte related functions among 96 tolerant samples. This signature was further supported through a cross-validation approach, yielding 92.5% accuracy independent of the study of origin. Experimental validation, performed on new tolerant samples and using a selection of the top-20 biomarkers, returned 91.7% of good classification. Beyond the confirmation of B-cell involvement, our data also indicated participation of other cell subsets in tolerance. Thus, the use of the top 20 biomarkers, mostly centered on B cells, may provide a common and standardized tool towards personalized medicine for the monitoring of tolerant or low-risk patients among kidney allotransplant recipients. These data point to a global preservation of genes favoring the maintenance of a homeostatic and 'healthy' environment in tolerant patients and may contribute to a better understanding of tolerance maintenance mechanisms.
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http://dx.doi.org/10.1038/ki.2014.395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424816PMC
May 2015

Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease.

Mol Nutr Food Res 2015 Feb 9;59(2):293-302. Epub 2014 Dec 9.

Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Vandœuvre-lès-Nancy, France.

Scope: Our study aims to investigate molecular events associated to methyl donor deficiency (MDD) by analyzing the transcriptome and the methylome of MDD rats in liver.

Methods And Results: Twenty-one-day-old rats born to mothers fed either with a standard diet or a MDD diet during gestation and lactation were compared. From a total of 44 000 probes for 26 456 genes, we found two gene clusters in MDD rats whose expression levels had significant differences compared with controls: 3269 overexpressed (p < 0.0009) and 2841 underexpressed (p < 0.0004) genes. Modifications of DNA methylation were found in the promoter regions of 1032 genes out of 14 981 genes. Ontological analyses revealed that these genes are mainly involved in glucose and lipid metabolism, nervous system, coagulation, ER stress, and mitochondrial function.

Conclusion: Putative master genes exhibiting changes in both gene expression and DNA methylation are limited to 266 genes and are mainly involved in the renin-angiotensin system (n = 3), mitochondrion metabolism (n = 18), and phospholipid homeostasis (n = 3). Most of these master genes participate in nonalcoholic fatty liver disease. The adverse effects of MDD on the metabolic process indicate the beneficial impact of folate and vitamin B12, especially during the perinatal period.
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http://dx.doi.org/10.1002/mnfr.201400483DOI Listing
February 2015

Genome-wide analysis of host mRNA translation during hepatitis C virus infection.

J Virol 2013 Jun 3;87(12):6668-77. Epub 2013 Apr 3.

Equipe 4271, Université de Nantes, Paris, France.

In the model of Huh-7.5.1 hepatocyte cells infected by the JFH1 hepatitis C virus (HCV) strain, transcriptomic and proteomic studies have revealed modulations of pathways governing mainly apoptosis and cell cycling. Differences between transcriptomic and proteomic studies pointed to regulations occurring at the posttranscriptional level, including the control of mRNA translation. In this study, we investigated at the genome-wide level the translational regulation occurring during HCV infection. Sucrose gradient ultracentrifugation followed by microarray analysis was used to identify translationally regulated mRNAs (mRNAs associated with ribosomes) from JFH1-infected and uninfected Huh-7.5.1 cells. Translationally regulated mRNAs were found to correspond to genes enriched in specific pathways, including vesicular transport and posttranscriptional regulation. Interestingly, the strongest translational regulation was found for mRNAs encoding proteins involved in pre-mRNA splicing, mRNA translation, and protein folding. Strikingly, these pathways were not previously identified, through transcriptomic studies, as being modulated following HCV infection. Importantly, the observed changes in host mRNA translation were directly due to HCV replication rather than to HCV entry, since they were not observed in JFH1-infected Huh-7.5.1 cells treated with a potent HCV NS3 protease inhibitor. Overall, this study highlights the need to consider, beyond transcriptomic or proteomic studies, the modulation of host mRNA translation as an important aspect of HCV infection.
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http://dx.doi.org/10.1128/JVI.00538-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676112PMC
June 2013

Profiling of androgen response in rainbow trout pubertal testis: relevance to male gonad development and spermatogenesis.

PLoS One 2013 3;8(1):e53302. Epub 2013 Jan 3.

INRA, UR1037 LPGP, SFR Biosit, Biogenouest, Campus de Beaulieu, Rennes, France.

The capacity of testicular somatic cells to promote and sustain germ cell differentiation is largely regulated by sexual steroids and notably androgens. In fish species the importance of androgens is emphasized by their ability to induce sex reversal of the developing fries and to trigger spermatogenesis. Here we studied the influence of androgens on testicular gene expression in trout testis using microarrays. Following treatment of immature males with physiological doses of testosterone or 11-ketotestosterone, 418 genes that exhibit changes in expression were identified. Interestingly, the activity of testosterone appeared stronger than that of 11-ketotestosterone. Expression profiles of responsive genes throughout testis development and in isolated germ cells confirmed androgens to mainly affect gene expression in somatic cells. Furthermore, specific clusters of genes that exhibit regulation coincidently with changes in the natural circulating levels of androgens during the reproductive cycle were highlighted, reinforcing the physiological significance of these data. Among somatic genes, a phylogenetic footprinting study identified putative androgen response elements within the proximal promoter regions of 42 potential direct androgen target genes. Finally, androgens were also found to alter the germ line towards meiotic expression profiles, supporting the hypothesis of a role for the somatic responsive genes in driving germ cell fate. This study significantly increases our understanding of molecular pathways regulated by androgens in vertebrates. The highly cyclic testicular development in trout together with functions associated with regulated genes reveal potential mechanisms for androgen actions in tubule formation, steroid production, germ cell development and sperm secretion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536770PMC
August 2013

Genomic assessment of human cumulus cell marker genes as predictors of oocyte developmental competence: impact of various experimental factors.

PLoS One 2012 27;7(7):e40449. Epub 2012 Jul 27.

INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France.

Background: Single embryo transfer (SET) is the most successful way to reduce the frequency of multiple pregnancies following in vitro fertilisation. However, selecting the embryo for SET with the highest chances of pregnancy remains a difficult challenge since morphological and kinetics criteria provide poor prediction of both developmental and implantation ability. Partly through the expression of specific genes, the oocyte-cumulus interaction helps the oocyte to acquire its developmental competence. Our aim was therefore to identify at the level of cumulus cells (CCs) genes related to oocyte developmental competence.

Methodology/principal Findings: 197 individual CCs were collected from 106 patients undergoing an intra-cytoplasmic sperm injection procedure. Gene expression of CCs was studied using microarray according to the nuclear maturity of the oocyte (immature vs. mature oocyte) and to the developmental competence of the oocyte (ability to reach the blastocyst stage after fertilisation). Microarray study was followed by a meta-analysis of the behaviour of these genes in other datasets available in Gene Expression Omnibus which showed the consistency of this list of genes. Finally, 8 genes were selected according to oocyte developmental competence from the 308 differentially expressed genes (p<0.0001) for further validation by quantitative PCR (qPCR). Three of these 8 selected genes were validated as potential biomarkers (PLIN2, RGS2 and ANG). Experimental factors such as inter-patient and qPCR series variability were then assessed using the Generalised Linear Mixed Model procedure, and only the expression level of RGS2 was confirmed to be related to oocyte developmental competence. The link between biomarkers and pregnancy was finally evaluated and level of RGS2 expression was also correlated with clinical pregnancy.

Conclusion/significance: RGS2, known as a regulator of G protein signalling, was the only gene among our 8 selected candidates biomarkers of oocyte competence to cover many factors of variability, including inter-patient factors and experimental conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407221PMC
April 2013

MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation.

Blood 2012 May 9;119(20):4619-24. Epub 2012 Mar 9.

Hematologie biologique, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Ave. Claude Vellefaux, Paris, France.

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC(+)). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC(+) rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC(-) DLBCL patients, the MYC(+) DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC(+) DLBCL patients than those in the MYC(-) DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC(+) DLBCL patients have a significant inferior prognosis than MYC(-) DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.
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http://dx.doi.org/10.1182/blood-2012-01-406033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815438PMC
May 2012

Immune response and mitochondrial metabolism are commonly deregulated in DMD and aging skeletal muscle.

PLoS One 2011 9;6(11):e26952. Epub 2011 Nov 9.

INSERM, UMR915, Nantes, France.

Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212519PMC
April 2012

High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies.

PLoS One 2011 22;6(9):e25181. Epub 2011 Sep 22.

Inserm U613, Brest, France.

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178625PMC
February 2012

The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study.

J Clin Oncol 2011 Nov 26;29(31):4079-87. Epub 2011 Sep 26.

Hematology, APHP, Hôpital Saint Louis, INSERM U728, IUH, Paris, France.

Purpose: To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial.

Patients And Methods: Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model.

Results: Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) -like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients.

Conclusion: COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.
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http://dx.doi.org/10.1200/JCO.2011.35.4423DOI Listing
November 2011

Nitric oxide and calcium participate in the fine regulation of mitochondrial biogenesis in follicular thyroid carcinoma cells.

J Biol Chem 2011 May 31;286(20):18229-39. Epub 2011 Mar 31.

INSERM UMR694, Centre Hospitalier Universitaire d’Angers, F-49033 Angers, France.

Members of the peroxisome proliferator-activated receptor γ coactivator-1 family (i.e. PGC-1α, PGC-1β, and the PGC-1-related coactivator (PRC)) are key regulators of mitochondrial biogenesis and function. These regulators serve as mediators between environmental or endogenous signals and the transcriptional machinery governing mitochondrial biogenesis. The FTC-133 and RO82 W-1 follicular thyroid carcinoma cell lines, which present significantly different numbers of mitochondria, metabolic mechanisms, and expression levels of PRC and PGC-1α, may employ retrograde signaling in response to respiratory dysfunction. Nitric oxide (NO) and calcium have been hypothesized to participate in this activity. We investigated the effects of the S-nitroso-N-acetyl-DL-penicillamine-NO donor, on the expression of genes involved in mitochondrial biogenesis and cellular metabolic functions in FTC-133 and RO82 W-1 cells by measuring lactate dehydrogenase and cytochrome c oxidase (COX) activities. We studied the action of ionomycin and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM) (i.e. a calcium ionophore and a cytosolic calcium chelator) on whole genome expression and mitochondrial biogenesis in RO82 W-1 cells. COX activity and the dynamics of endoplasmic reticulum and mitochondrial networks were analyzed in regard to calcium-modulating treatments. In the FTC-133 and RO82 W-1 cells, the mitochondrial biogenesis induced by NO was mainly related to PRC expression as a retrograde mitochondrial signaling. Ionomycin diminished COX activity and negatively regulated PRC-mediated mitochondrial biogenesis in RO82 W-1 cells, whereas BAPTA/AM produced the opposite effects with a reorganization of the mitochondrial network. This is the first demonstration that NO and calcium regulate mitochondrial biogenesis through the PRC pathway in thyroid cell lines.
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http://dx.doi.org/10.1074/jbc.M110.217521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093895PMC
May 2011

Identification of proteomic signatures of mantle cell lymphoma, small lymphocytic lymphoma, and marginal zone lymphoma biopsies by surface enhanced laser desorption/ionization-time of flight mass spectrometry.

Leuk Lymphoma 2011 Apr 11;52(4):648-58. Epub 2011 Jan 11.

INSERM U836, Equipe 7 Université Joseph Fourier, Grenoble, France.

Mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL) are small B-cell non-Hodgkin lymphomas (NHLs) that may be difficult to distinguish. In order to identify specific proteomic biomarkers, differential proteomic analysis of these three NHLs was performed using surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). Whole cell lysates obtained from 18 MCL, 20 SLL, and 20 MZL biopsies were applied on two different ProteinChips (cationic and anionic). Hierarchical clustering and discriminating scores combined with an innovative bio-informatics microdissection strategy allowed us to distinguish specific lymphoma proteomic signatures based on the expression of 37 protein peaks. SELDI-assisted protein purification combined with nano-liquid chromatography (LC) quadrupole-time of flight tandem mass spectrometry (Q-TOF MS/MS) was used to identify proteins overexpressed in both MCL and SLL tumors. Among them two histones, H2B and H4, were identified in MCL tumor biopsies and the signal recognition particle 9 kDa protein, SRP9, in SLL tumor biopsies.
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http://dx.doi.org/10.3109/10428194.2010.549256DOI Listing
April 2011

Meta-analysis of muscle transcriptome data using the MADMuscle database reveals biologically relevant gene patterns.

BMC Genomics 2011 Feb 16;12:113. Epub 2011 Feb 16.

INSERM, U915, Nantes, F-44000 France.

Background: DNA microarray technology has had a great impact on muscle research and microarray gene expression data has been widely used to identify gene signatures characteristic of the studied conditions. With the rapid accumulation of muscle microarray data, it is of great interest to understand how to compare and combine data across multiple studies. Meta-analysis of transcriptome data is a valuable method to achieve it. It enables to highlight conserved gene signatures between multiple independent studies. However, using it is made difficult by the diversity of the available data: different microarray platforms, different gene nomenclature, different species studied, etc.

Description: We have developed a system tool dedicated to muscle transcriptome data. This system comprises a collection of microarray data as well as a query tool. This latter allows the user to extract similar clusters of co-expressed genes from the database, using an input gene list. Common and relevant gene signatures can thus be searched more easily. The dedicated database consists in a large compendium of public data (more than 500 data sets) related to muscle (skeletal and heart). These studies included seven different animal species from invertebrates (Drosophila melanogaster, Caenorhabditis elegans) and vertebrates (Homo sapiens, Mus musculus, Rattus norvegicus, Canis familiaris, Gallus gallus). After a renormalization step, clusters of co-expressed genes were identified in each dataset. The lists of co-expressed genes were annotated using a unified re-annotation procedure. These gene lists were compared to find significant overlaps between studies.

Conclusions: Applied to this large compendium of data sets, meta-analyses demonstrated that conserved patterns between species could be identified. Focusing on a specific pathology (Duchenne Muscular Dystrophy) we validated results across independent studies and revealed robust biomarkers and new pathways of interest. The meta-analyses performed with MADMuscle show the usefulness of this approach. Our method can be applied to all public transcriptome data.
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http://dx.doi.org/10.1186/1471-2164-12-113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049149PMC
February 2011

MADGene: retrieval and processing of gene identifier lists for the analysis of heterogeneous microarray datasets.

Bioinformatics 2011 Mar 6;27(5):725-6. Epub 2011 Jan 6.

INSERM U915, IRT-UN, University of Nantes, France.

Unlabelled: MADGene is a software environment comprising a web-based database and a java application. This platform aims at unifying gene identifiers (ids) and performing gene set analysis. MADGene allows the user to perform inter-conversion of clone and gene ids over a large range of nomenclatures relative to 17 species. We propose a set of 23 functions to facilitate the analysis of gene sets and we give two microarray applications to show how MADGene can be used to conduct meta-analyses.

Availability: The MADGene resources are freely available online from http://www.madtools.org, a website dedicated to the analysis and annotation of DNA microarray data.
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http://dx.doi.org/10.1093/bioinformatics/btq710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042180PMC
March 2011

Nutritional programming in the rat is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus.

PLoS One 2010 Oct 21;5(10):e13537. Epub 2010 Oct 21.

INRA, UMR1280 Physiologie des Adaptations Nutritionnelles, Université de Nantes, Nantes Atlantique Université, Nantes, France.

Background: Nutrient deficiency during perinatal development is associated with an increased risk to develop obesity, diabetes and hypertension in the adulthood. However, the molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown.

Methodology/principal Findings: Given the essential role of the hypothalamus in the integration of nutritional, endocrine and neuronal cues, here we have analyzed the profile of the hypothalamus transcriptome in 180 days-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet through pregnancy and lactation. From a total of 26 209 examined genes, 688 were up-regulated and 309 down-regulated (P<0.003) by early protein restriction. Further bioinformatic analysis of the data revealed that perinatal protein restriction permanently alters the expression of two gene clusters regulating common cellular processes. The first one includes several gate keeper genes regulating insulin signaling and nutrient sensing. The second cluster encompasses a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel which, in addition, link temporal and nutritional cues to metabolism through their tight interaction with the circadian clock.

Conclusions/significance: Collectively, these results indicate that the programming of the hypothalamic circuits regulating energy homeostasis is a key step in the development of obesity associated with malnutrition in early life and provide a valuable resource for further investigating the role of the hypothalamus in the programming of the metabolic syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013537PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958833PMC
October 2010

A parallel scheme for comparing transcription factor binding sites matrices.

J Bioinform Comput Biol 2010 Jun;8(3):485-502

Institut du thorax, INSERM U 915, Université de Nantes, France.

Gene regulation implies many mechanisms. Their identification is a crucial task to construct regulatory networks, and is necessary to understand the pathology in many cases. This requires the identification of transcription factors that play a role in regulation. Numerous motif discovery tools are now available. Combining efficiently their results appears useful for comparing and clustering these motifs in order to reduce redundancies and to identify the corresponding transcription factor. We develop a method that produces, compares and clusters a set of motifs and identifies some close motifs in databases like JASPAR and the public version of Transfac. Unlike previous comparison methods, where each matrix column is compared independently, we have developed a global method to compare motifs that also helps to reduce the number of false positives. We also propose an original graph motif model that generalizes the classical position specific pattern matrices. Finally, we present an application of our method to study ChIP-chip data sets in the context of an eukaryotic organism.
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http://dx.doi.org/10.1142/s0219720010004689DOI Listing
June 2010