28 results on '"Jonathan Gaucher"'
Search Results
2. Long-term intermittent hypoxia in mice induces inflammatory pathways implicated in sleep apnea and steatohepatitis in humans
- Author
-
Jonathan Gaucher, Emilie Montellier, Guillaume Vial, Florent Chuffart, Maëlle Guellerin, Sophie Bouyon, Emeline Lemarie, Yoshiki Yamaryo Botté, Aya Dirani, Raoua Ben Messaoud, Marie Joyeux Faure, Diane Godin Ribuot, Charlotte Costentin, Renaud Tamisier, Cyrille Y. Botté, Saadi Khochbin, Sophie Rousseaux, and Jean-Louis Pépin
- Subjects
Natural sciences ,Biological sciences ,Physiology ,Animal physiology ,Human Physiology ,Science - Abstract
Summary: Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH), an independent risk factor for non-alcoholic fatty liver disease (NAFLD). While the molecular links between IH and NAFLD progression are unclear, immune cell-driven inflammation plays a crucial role in NAFLD pathogenesis. Using lean mice exposed to long-term IH and a cohort of lean OSA patients (n = 71), we conducted comprehensive hepatic transcriptomics, lipidomics, and targeted serum proteomics. Significantly, we demonstrated that long-term IH alone can induce NASH molecular signatures found in human steatohepatitis transcriptomic data. Biomarkers (PPARs, NRFs, arachidonic acid, IL16, IL20, IFNB, TNF-α) associated with early hepatic and systemic inflammation were identified. This molecular link between IH, sleep apnea, and steatohepatitis merits further exploration in clinical trials, advocating for integrating sleep apnea diagnosis in liver disease phenotyping. Our unique signatures offer potential diagnostic and treatment response markers, highlighting therapeutic targets in the comorbidity of NAFLD and OSA.
- Published
- 2024
- Full Text
- View/download PDF
3. Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration
- Author
-
Jonathan Gaucher, Guillaume Vial, Emilie Montellier, Maëlle Guellerin, Sophie Bouyon, Emeline Lemarie, Véronique Pelloux, Anne Bertrand, Karin Pernet-Gallay, Frederic Lamarche, Anne-Laure Borel, Claire Arnaud, Elise Belaidi, Karine Clément, Diane Godin Ribuot, Judith Aron-Wisnewsky, and Jean-Louis Pépin
- Subjects
sleep apnea ,intermittent hypoxia (IH) ,liver ,transcriptome ,mitochondria ,Nuclear Respiratory Factor (NRF) ,Medicine (General) ,R5-920 - Abstract
Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.
- Published
- 2022
- Full Text
- View/download PDF
4. Physiological Impact of a Synthetic Elastic Protein in Arterial Diseases Related to Alterations of Elastic Fibers: Effect on the Aorta of Elastin-Haploinsufficient Male and Female Mice
- Author
-
Quentin Boëté, Ming Lo, Kiao-Ling Liu, Guillaume Vial, Emeline Lemarié, Maxime Rougelot, Iris Steuckardt, Olfa Harki, Axel Couturier, Jonathan Gaucher, Sophie Bouyon, Alexandra Demory, Antoine Boutin-Paradis, Naima El Kholti, Aurore Berthier, Jean-Louis Pépin, Anne Briançon-Marjollet, Elise Lambert, Romain Debret, and Gilles Faury
- Subjects
aorta ,structure ,mechanics ,reactivity ,elastic fiber synthesis/repair ,pharmacotherapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Elastic fibers, made of elastin (90%) and fibrillin-rich microfibrils (10%), are the key extracellular components, which endow the arteries with elasticity. The alteration of elastic fibers leads to cardiovascular dysfunctions, as observed in elastin haploinsufficiency in mice (Eln+/-) or humans (supravalvular aortic stenosis or Williams–Beuren syndrome). In Eln+/+ and Eln+/- mice, we evaluated (arteriography, histology, qPCR, Western blots and cell cultures) the beneficial impact of treatment with a synthetic elastic protein (SEP), mimicking several domains of tropoelastin, the precursor of elastin, including hydrophobic elasticity-related domains and binding sites for elastin receptors. In the aorta or cultured aortic smooth muscle cells from these animals, SEP treatment induced a synthesis of elastin and fibrillin-1, a thickening of the aortic elastic lamellae, a decrease in wall stiffness and/or a strong trend toward a reduction in the elastic lamella disruptions in Eln+/- mice. SEP also modified collagen conformation and transcript expressions, enhanced the aorta constrictive response to phenylephrine in several animal groups, and, in female Eln+/- mice, it restored the normal vasodilatory response to acetylcholine. SEP should now be considered as a biomimetic molecule with an interesting potential for future treatments of elastin-deficient patients with altered arterial structure/function.
- Published
- 2022
- Full Text
- View/download PDF
5. Adipose tissue as a key player in obstructive sleep apnoea
- Author
-
Silke Ryan, Claire Arnaud, Susan F. Fitzpatrick, Jonathan Gaucher, Renaud Tamisier, and Jean-Louis Pépin
- Subjects
Diseases of the respiratory system ,RC705-779 - Abstract
Obstructive sleep apnoea (OSA) is a major health concern worldwide and adversely affects multiple organs and systems. OSA is associated with obesity in >60% of cases and is independently linked with the development of numerous comorbidities including hypertension, arrhythmia, stroke, coronary heart disease and metabolic dysfunction. The complex interaction between these conditions has a significant impact on patient care and mortality. The pathophysiology of cardiometabolic complications in OSA is still incompletely understood; however, the particular form of intermittent hypoxia (IH) observed in OSA, with repetitive short cycles of desaturation and re-oxygenation, probably plays a pivotal role. There is fast growing evidence that IH mediates some of its detrimental effects through adipose tissue inflammation and dysfunction. This article aims to summarise the effects of IH on adipose tissue in experimental models in a comprehensive way. Data from well-designed controlled trials are also reported with the final goal of proposing new avenues for improving phenotyping and personalised care in OSA.
- Published
- 2019
- Full Text
- View/download PDF
6. The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world
- Author
-
Gal Manella, Saar Ezagouri, Benoit Champigneulle, Jonathan Gaucher, Monique Mendelson, Emeline Lemarie, Emeric Stauffer, Aurélien Pichon, Connor A. Howe, Stéphane Doutreleau, Marina Golik, Samuel Verges, Gad Asher, Weizmann Institute of Science [Rehovot, Israël], Hypoxie et PhysioPathologie (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire 'Mobilité, Vieillissement, Exercice' (MOVE), Université de Poitiers, University of British Columbia (UBC), ANR-12-TECS-0010,PASITHEA,Traitement personnalisé et adaptatif par stimulation kinesthésique pour les syndromes d'apnée du sommeil, basé sur un moniteur Holter cardio-respiratoire(2012), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-19-CE14-0037,TEMPORISE,Interaction entre l'hypoxie et l'horloge biologique dans le développement de la maladie du foie liée à l'apnée du sommeil(2019), SALAS, Danielle, Technologie pour la santé et l'autonomie - Traitement personnalisé et adaptatif par stimulation kinesthésique pour les syndromes d'apnée du sommeil, basé sur un moniteur Holter cardio-respiratoire - - PASITHEA2012 - ANR-12-TECS-0010 - TecSan - VALID, IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID, and Interaction entre l'hypoxie et l'horloge biologique dans le développement de la maladie du foie liée à l'apnée du sommeil - - TEMPORISE2019 - ANR-19-CE14-0037 - AAPG2019 - VALID
- Subjects
lowlanders ,[SDV]Life Sciences [q-bio] ,Altitude ,circadian clocks ,daily rhythms ,CIBERSORTx ,General Biochemistry, Genetics and Molecular Biology ,immune response ,whole-blood transcriptomics ,[SDV] Life Sciences [q-bio] ,high altitude ,clock genes ,Humans ,CP: Molecular biology ,Hypoxia ,Transcriptome - Abstract
International audience; High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level. We find that high altitude vastly affects the blood transcriptome and, unexpectedly, does not necessarily follow a monotonic response to altitude elevation. Importantly, we observe daily variance in gene expression, especially immune-related genes, which is largely altitude dependent. Moreover, using a digital cytometry approach, we estimate relative changes in abundance of different cell types and find that the response of several immune cell types is time- and altitude dependent. Taken together, our data provide evidence for interaction between the transcriptional response to hypoxia and the time of day in humans.
- Published
- 2022
7. Digital markers of sleep architecture to characterize the impact of different lockdown regimens on sleep health during the COVID-19 pandemic
- Author
-
Jean-Louis Pépin, Sébastien Bailly, Emmanuel Mignot, Jonathan Gaucher, Alexandre Chouraki, Mallory Cals-Maurette, Raoua Ben Messaoud, Renaud Tamisier, Pierrick J Arnal, SALAS, Danielle, and MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID
- Subjects
[SDV] Life Sciences [q-bio] ,Physiology (medical) ,Neurology (clinical) - Published
- 2022
8. Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration
- Author
-
Jonathan Gaucher, Guillaume Vial, Emilie Montellier, Maëlle Guellerin, Sophie Bouyon, Emeline Lemarie, Véronique Pelloux, Anne Bertrand, Karin Pernet-Gallay, Frederic Lamarche, Anne-Laure Borel, Claire Arnaud, Elise Belaidi, Karine Clément, Diane Godin Ribuot, Judith Aron-Wisnewsky, and Jean-Louis Pépin
- Subjects
mitochondria ,Medicine (General) ,Nuclear Respiratory Factor (NRF) ,R5-920 ,intermittent hypoxia (IH) ,General Medicine ,sleep apnea ,liver ,transcriptome - Abstract
Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.
- Published
- 2021
9. Targeting the interplay between metabolism and epigenetics in cancer
- Author
-
Emilie Montellier and Jonathan Gaucher
- Subjects
0301 basic medicine ,Cancer Research ,Carcinogenesis ,business.industry ,Metabolism ,Epigenesis, Genetic ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cell metabolism ,Oncology ,Tumor progression ,Neoplasms ,030220 oncology & carcinogenesis ,Gene expression ,Cancer research ,Animals ,Humans ,Medicine ,Epigenetics ,business - Abstract
Metabolic perturbation is a hallmark of cancer favoring tumor progression. It is now demonstrated that cell metabolism has an impact on gene expression through epigenetic modifications. In this review, we expose recent evidences of metabolic-driven epigenetic perturbations in cancer and subsequent therapeutic opportunities.The intimate link between metabolism and epigenetics and its rewiring in carcinogenesis is a hot topic. Chromatin-modifying enzymes involved in the dynamics of methylation or acetylation require small metabolites as cofactors or substrates, thus orchestrating the integration between epigenetic and transcriptional states. Mutations in metabolic enzymes such as isocitrate dehydrogenase 1 and 2 cause the accumulation of metabolites that upset the balance of histone and DNA methylation, thus generating widespread deregulation of epigenetically controlled gene expression. Additionally, modifications of catalytic activity and subcellular localization of metabolic enzymes in cancer can impact on epigenetic modifications and gene expression programs to favor tumor progression.The interplay between metabolism and epigenetics and its molecular characterization in cancer cells identifies potential targets for the development of new therapies.
- Published
- 2019
10. Greatest changes in objective sleep architecture during COVID-19 lockdown in night owls with increased REM sleep
- Author
-
Raoua Ben Messaoud, Ernest Mordret, Renaud Tamisier, Pierrick J. Arnal, Sébastien Bailly, Emmanuel Mignot, Jean-Louis Pépin, Jonathan Gaucher, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Dreem SAS, Stanford University, and ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019)
- Subjects
medicine.medical_specialty ,Sleep, REM ,Polysomnography ,Audiology ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Humans ,Medicine ,AcademicSubjects/MED00385 ,Pandemics ,sleep monitoring headband ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Sleep restriction ,Slow-wave sleep ,0303 health sciences ,Sleep Stages ,medicine.diagnostic_test ,SARS-CoV-2 ,AcademicSubjects/SCI01870 ,business.industry ,COVID-19 ,Chronotype ,Sleep in non-human animals ,Sleep deprivation ,Communicable Disease Control ,chronotype ,Original Article ,sleep architecture ,Neurology (clinical) ,Sleep onset ,medicine.symptom ,Sleep ,business ,Covid-19 lockdown ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery ,AcademicSubjects/MED00370 - Abstract
Study Objectives The COVID-19 pandemic has had dramatic effects on society and people’s daily habits. In this observational study, we recorded objective data on sleep macro- and microarchitecture repeatedly over several nights before and during the COVID-19 government-imposed lockdown. The main objective was to evaluate changes in patterns of sleep duration and architecture during home confinement using the pre-confinement period as a control. Methods Participants were regular users of a sleep-monitoring headband that records, stores, and automatically analyzes physiological data in real time, equivalent to polysomnography. We measured sleep onset duration, total sleep time, duration of sleep stages (N2, N3, and rapid eye movement [REM]), and sleep continuity. Via the user’s smartphone application, participants filled in questionnaires on how lockdown changed working hours, eating behavior, and daily life at home. They also filled in the Insomnia Severity Index, reduced Morningness–Eveningness Questionnaire, and Hospital Anxiety and Depression Scale questionnaires, allowing us to create selected subgroups. Results The 599 participants were mainly men (71%) of median age 47 (interquartile range: 36–59). Compared to before lockdown, during lockdown individuals slept more overall (mean +3·83 min; SD: ±1.3), had less deep sleep (N3), more light sleep (N2), and longer REM sleep (mean +3·74 min; SD: ±0.8). They exhibited less weekend-specific changes, suggesting less sleep restriction during the week. Changes were most pronounced in individuals reporting eveningness preferences, suggesting relative sleep deprivation in this population and exacerbated sensitivity to societal changes. Conclusion This unique dataset should help us understand the effects of lockdown on sleep architecture and on our health.
- Published
- 2021
11. S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling
- Author
-
Hitoshi Okamura, Axel Imhof, Jiejun Shi, Kenichiro Kinouchi, Marlene Cervantes, Kakeru Ito, Carolina Magdalen Greco, Rika Kojima, Pierre Baldi, Jean-Michel Fustin, Kevin B. Koronowski, Paolo Sassone-Corsi, Jonathan Gaucher, Wei Li, Suman Ranjit, Nicholas Ceglia, Ignasi Forné, Muntaha Samad, and Enrico Gratton
- Subjects
Methyltransferase ,1.1 Normal biological development and functioning ,Circadian clock ,CLOCK Proteins ,Chromatin remodeling ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Methionine ,Underpinning research ,Circadian Clocks ,Gene expression ,Genetics ,Animals ,Circadian rhythm ,cardiovascular diseases ,Molecular Biology ,Research Articles ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Chemistry ,Suprachiasmatic nucleus ,Adenosylhomocysteinase ,Human Genome ,SciAdv r-articles ,ARNTL Transcription Factors ,Cell Biology ,Chromatin Assembly and Disassembly ,S-Adenosylhomocysteine ,Chromatin ,3. Good health ,Cell biology ,nervous system diseases ,Circadian Rhythm ,Sleep Research ,030217 neurology & neurosurgery ,Research Article - Abstract
The S-adenosylhomocysteine (SAH) hydrolyzing enzyme AHCY functionally links the circadian clock to methionine metabolism., Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)–dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.
- Published
- 2020
12. Obstructive sleep apnea, chronic obstructive pulmonary disease and NAFLD: an individual participant data meta-analysis
- Author
-
François Goupil, Jean-Louis Pépin, Claire Alizon, Marc Le Vaillant, Sébastien Bailly, Acya Bizieux-Thaminy, Charlotte E. Costentin, Marie-Pierre Humeau, Renaud Tamisier, Thierry Pigeanne, Jérôme Boursier, Meriem Benmerad, Sandrine Jaffre, Frédéric Gagnadoux, Ingrid Jullian-Desayes, Jonathan Gaucher, Marie Joyeux-Faure, Wojciech Trzepizur, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Institut Recherche en Santé Respiratoire des Pays de la Loire ( IRSRPL), Centre hospitalier universitaire de Nantes (CHU Nantes), Pôle Santé des Olonnes, Centre Hospitalier Départemental site de la Roche-sur-Yon (CHD de la Roche-sur-Yon), Nouvelles Cliniques Nantaises - NCN [Nantes], Centre Hospitalier de Cholet, Centre Hospitalier Le Mans (CH Le Mans), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019)
- Subjects
Male ,medicine.medical_specialty ,Polysomnography ,Gastroenterology ,03 medical and health sciences ,Liver disease ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,2. Zero hunger ,COPD ,Sleep Apnea, Obstructive ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,medicine.diagnostic_test ,FibroTest ,business.industry ,Sleep apnea ,General Medicine ,medicine.disease ,respiratory tract diseases ,3. Good health ,Obstructive sleep apnea ,030228 respiratory system ,Diabetes Mellitus, Type 2 ,Steatosis ,business ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Rationale Chronic intermittent hypoxia occurring in obstructive sleep apnea (OSA) is independently associated with nonalcoholic fatty liver disease (NAFLD). Chronic obstructive pulmonary disease (COPD) has also been suggested to be linked with liver disease. Objective In this individual participant data meta-analysis, we investigated the association between liver damage and OSA and COPD severity. Methods and measurements Patients suspected of OSA underwent polysomnography (PSG) or home sleep apnea testing (HSAT). Non-invasive tests were used to evaluate liver steatosis (Hepatic Steatosis Index) and fibrosis (Fibrotest or FibroMeter). An individual participant data meta-analysis approach was used to determine if the severity of OSA/COPD affects the type and severity of liver disease. Results were confirmed by multivariate and causal mediation analysis. Sub-group analyses were performed to investigate specific populations. Main results Among 2120 patients, 1584 had steatosis (75%). In multivariable analysis, risk factors for steatosis were an apnea-hypopnea index (AHI) > 5/h, body mass index (BMI) > 26 kg/m2, age, type 2 diabetes (all p-values 26 kg/m2, age, male gender, and type 2 diabetes (all p-values 30/h and COPD stage 1 was associated with an increased risk of steatosis. Conclusion This meta-analysis confirms the strong association between steatosis and the severity of OSA. The relation between OSA and fibrosis is mainly due to BMI as shown by causal mediation analysis.
- Published
- 2020
13. Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake
- Author
-
Paolo Sassone-Corsi, Pierre Baldi, Kenichiro Kinouchi, Ignasi Forné, Emilie Montellier, Jonathan Gaucher, Carolina Magdalen Greco, Axel Imhof, Shahaf Peleg, Andreas Schmidt, Nicholas Ceglia, and Selma Masri
- Subjects
Male ,medicine.medical_specialty ,Alcohol Drinking ,Chronic Liver Disease and Cirrhosis ,Binge drinking ,Biology ,Inbred C57BL ,liver ,Oral and gastrointestinal ,Transcriptome ,chemistry.chemical_compound ,Mice ,Alcohol Use and Health ,Substance Misuse ,Internal medicine ,medicine ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,Circadian rhythm ,Ethanol metabolism ,Aetiology ,acetylation ,Nutrition ,Sterol Regulatory Element Binding Proteins ,Multidisciplinary ,Ethanol ,alcohol ,Liver Disease ,Metabolism ,Biological Sciences ,Sterol regulatory element-binding protein ,Circadian Rhythm ,Mice, Inbred C57BL ,Stroke ,Alcoholism ,Endocrinology ,circadian ,Good Health and Well Being ,chemistry ,Liver ,Sleep Research ,Digestive Diseases ,Reprogramming ,metabolism - Abstract
Binge drinking and chronic exposure to ethanol contribute to alcoholic liver diseases (ALDs). A potential link between ALDs and circadian disruption has been observed, though how different patterns of alcohol consumption differentially impact hepatic circadian metabolism remains virtually unexplored. Using acute versus chronic ethanol feeding, we reveal differential reprogramming of the circadian transcriptome in the liver. Specifically, rewiring of diurnal SREBP transcriptional pathway leads to distinct hepatic signatures in acetyl-CoA metabolism that are translated into the subcellular patterns of protein acetylation. Thus, distinct drinking patterns of alcohol dictate differential adaptation of hepatic circadian metabolism.
- Published
- 2019
14. Molecular Cogs: Interplay between Circadian Clock and Cell Cycle
- Author
-
Paolo Sassone-Corsi, Emilie Montellier, and Jonathan Gaucher
- Subjects
0301 basic medicine ,Cell division ,ARNTL Transcription Factors ,Cell growth ,Cell Cycle ,Circadian clock ,CLOCK Proteins ,Context (language use) ,Cell Biology ,Cell cycle ,Biology ,Circadian Rhythm ,03 medical and health sciences ,030104 developmental biology ,Circadian Clocks ,Animals ,Humans ,Circadian rhythm ,Neuroscience ,Cell Division ,Cell Proliferation - Abstract
The cell cycle and the circadian clock operate as biological oscillators whose timed functions are tightly regulated. Accumulating evidence illustrates the presence of molecular links between these two oscillators. This mutual interplay utilizes various coupling mechanisms, such as the use of common regulators. The connection between these two cyclic systems has unique interest in the context of aberrant cell proliferation since both of these oscillators are frequently misregulated in cancer cells. Further studies will provide deeper understanding of the detailed molecular connections between the cell cycle and the circadian clock and may also serve as a basis for the design of innovative therapeutic strategies.
- Published
- 2018
15. Intermittent hypoxia induces premature adipose tissue senescence leading to cardiac remodeling
- Author
-
M. Pini, Z. Mezdari, S. Naushad Khan, Y. Zhang, G. Derumeaux, D. Sawaki, Jonathan Gaucher, Sophie Bouyon, Elise Belaidi, Claire Arnaud, and J.L. Pépin
- Subjects
Senescence ,medicine.medical_specialty ,business.industry ,Adipose tissue ,Intermittent hypoxia ,medicine.disease_cause ,medicine.disease ,Muscle hypertrophy ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Fibrosis ,Internal medicine ,medicine ,Myocardial fibrosis ,Cardiology and Cardiovascular Medicine ,business ,Sirius Red ,Oxidative stress - Abstract
Introduction Obstructive sleep apnea is a growing worldwide health problem. The landmark feature of OSA is a chronic intermittent hypoxia (CIH) responsible for multiple organ damages including heart diseases. CIH profoundly alters both visceral adipose tissue (VAT) and heart structures and functions, but little is known regarding their interactions in the context of CIH. We recently showed that VAT senescence drives myocardial alterations through the release of profibrotic factors in aged mice. Thus, we aim at demonstrating that CIH induces a premature vWAT senescent phenotype, responsible for subsequent heart dysfunction. Methods In a first series of animals, ten-week old C57BL6 male mice (n = 10/group) were exposed to 14 days CIH protocol (8 hours daily, 5–21% cyclic inspired oxygen fraction, 60 seconds per cycle). In another series, mice were submitted to VAT surgical lipectomy or sham-surgery (n = 10/group) and then exposed to the same CIH protocol. VAT and heart were assessed by histology for fibrosis (Sirius red), cell hypertrophy (wheat-germ agglutinin) and reactive oxygen species (ROS) (4-HNE), and markers of senescence (p16, p21, p53), inflammation (CD68, Tnfa, Serpine1), fibrosis (Col1a1) and hypertrophy were also evaluated by RT-qPCR and western blot. Results CIH induced an increased macrophage infiltration in VAT, along with an increased expression of senescence markers, ROS production and gene expression of inflammatory and fibrogenic markers. This was associated with CIH-induced myocardial interstitial fibrosis and upregulation of profibrotic gene expression in myocardium. Interestingly, VAT lipectomy prevented CIH-induced myocardial fibrosis. Conclusion Short-term exposure to CIH is sufficient to induce both VAT remodelling, characterized by oxidative stress, inflammation and fibrosis, and cardiac interstitial fibrosis that was prevented by VAT lipectomy. This strongly suggest a causal crosstalk between CIH-induced VAT senescence and cardiac remodeling.
- Published
- 2020
16. Adipose tissue as a key player in obstructive sleep apnoea
- Author
-
Susan F. Fitzpatrick, Claire Arnaud, Silke Ryan, Renaud Tamisier, Jean-Louis Pépin, Jonathan Gaucher, University College Dublin [Dublin] (UCD), St Vincent's University Hospital, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU Grenoble, and SALAS, Danielle
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Adipose tissue ,Inflammation ,Bioinformatics ,Cardiovascular System ,03 medical and health sciences ,0302 clinical medicine ,Adipokines ,medicine ,Animals ,Humans ,Continuous positive airway pressure ,Lung ,Stroke ,Adiposity ,lcsh:RC705-779 ,Sleep Apnea, Obstructive ,Continuous Positive Airway Pressure ,business.industry ,Sleep apnea ,Intermittent hypoxia ,lcsh:Diseases of the respiratory system ,medicine.disease ,Obesity ,Pathophysiology ,respiratory tract diseases ,[SDV] Life Sciences [q-bio] ,Treatment Outcome ,030104 developmental biology ,Adipose Tissue ,Inflammation Mediators ,medicine.symptom ,Energy Metabolism ,business ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
International audience; Obstructive sleep apnoea (OSA) is a major health concern worldwide and adversely affects multiple organs and systems. OSA is associated with obesity in >60% of cases and is independently linked with the development of numerous comorbidities including hypertension, arrhythmia, stroke, coronary heart disease and metabolic dysfunction. The complex interaction between these conditions has a significant impact on patient care and mortality. The pathophysiology of cardiometabolic complications in OSA is still incompletely understood; however, the particular form of intermittent hypoxia (IH) observed in OSA, with repetitive short cycles of desaturation and re-oxygenation, probably plays a pivotal role. There is fast growing evidence that IH mediates some of its detrimental effects through adipose tissue inflammation and dysfunction. This article aims to summarise the effects of IH on adipose tissue in experimental models in a comprehensive way. Data from well-designed controlled trials are also reported with the final goal of proposing new avenues for improving phenotyping and personalised care in OSA.
- Published
- 2019
17. Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters
- Author
-
Di Zhang, Zhanyun Tang, Saadi Khochbin, Zhongyi Cheng, Guillaume Charbonnier, Carlo Petosa, Sophie Barral, Anne-Laure Vitte, Sophie Rousseaux, Robert G. Roeder, Thierry Buchou, Yingming Zhao, Tieming He, Shankang Qi, Daniel Panne, Sandrine Curtet, Afsaneh Goudarzi, Emilie Montellier, Jonathan Gaucher, Alexandra Debernardi, Denis Puthier, He Huang, Oh Kwang Kwon, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of Alabama [Tuscaloosa] (UA), Memorial Sloane Kettering Cancer Center [New York], Seoul National University [Seoul] (SNU), Ben May Department for Cancer Research, University of Chicago-Ben May Department for Cancer Research, The Jackson Laboratory [Bar Harbor] (JAX), Research Institute, Northeastern University [Shenyang], jingjie PTM Biolab, Hangzhou Dianzi University (HDU), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory [Grenoble] (EMBL), Laboratory of Biochemistry and Molecular Biology, Rockefeller University [New York], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
0301 basic medicine ,Male ,Transcriptional Activation ,Transcription, Genetic ,Protein Conformation ,SAP30 ,Article ,Epigenesis, Genetic ,Histone H4 ,Histones ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,Spermatocytes ,Histone H2A ,Histone code ,Nucleosome ,Animals ,Promoter Regions, Genetic ,Molecular Biology ,Genetics ,Binding Sites ,biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Lysine ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Acetylation ,Cell Differentiation ,Cell Biology ,Chromatin Assembly and Disassembly ,Bromodomain ,Cell biology ,Butyrates ,030104 developmental biology ,Histone ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Summary Recently discovered histone lysine acylation marks increase the functional diversity of nucleosomes well beyond acetylation. Here, we focus on histone butyrylation in the context of sperm cell differentiation. Specifically, we investigate the butyrylation of histone H4 lysine 5 and 8 at gene promoters where acetylation guides the binding of Brdt, a bromodomain-containing protein, thereby mediating stage-specific gene expression programs and post-meiotic chromatin reorganization. Genome-wide mapping data show that highly active Brdt-bound gene promoters systematically harbor competing histone acetylation and butyrylation marks at H4 K5 and H4 K8. Despite acting as a direct stimulator of transcription, histone butyrylation competes with acetylation, especially at H4 K5, to prevent Brdt binding. Additionally, H4 K5K8 butyrylation also marks retarded histone removal during late spermatogenesis. Hence, alternating H4 acetylation and butyrylation, while sustaining direct gene activation and dynamic bromodomain binding, could impact the final male epigenome features., Graphical Abstract, Highlights • Active gene TSSs are marked by competing H4 K5K8 acetylation and butyrylation • Histone butyrylation directly stimulates transcription • H4K5 butyrylation prevents binding of the testis specific gene expression-driver Brdt • H4K5K8 butyrylation is associated with delayed histone removal in spermatogenic cells, Histone butyrylation stimulates gene transcription while competing with acetylation at H4K5 to control Brdt bromodomain binding. Differential chromatin labeling with interchangeable H4 acylations is an important epigenetic regulatory mechanism controlling gene expression and chromatin reorganization.
- Published
- 2016
- Full Text
- View/download PDF
18. Impact of cardiac sympathetic denervation on IH-induced ischemic cardiomyopathy aggravation
- Author
-
Jonathan Gaucher, Jean-Louis Pépin, Claire Arnaud, Elise Belaidi, Maximin Détrait, and Sophie Bouyon
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Ischemic cardiomyopathy ,Ejection fraction ,business.industry ,Adrenergic ,Intermittent hypoxia ,medicine.disease ,Muscle hypertrophy ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Cardiology ,Medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Sirius Red - Abstract
Background Patients with sleep disordered breathing (SDB) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of SDB, enhances sympathetic activity, depletes cardiac adrenergic reserve and accelerates cardiac remodeling and dysfunction in a rat model of ischemic cardiomyopathy. In the present study, we aim at investigating whether specific cardiac sympathetic denervation (CSD) counteracts the IH-induced adrenergic reserve depletion and ischemic cardiomyopathy aggravation. Methods MI is induced in male Wistar rats by permanent ligation of the left coronary artery and CSD by ablation of the left middle cervical and stellate ganglions. After surgery, rats are exposed to 6 and 14 weeks IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N). Cardiac function and remodeling are evaluated by echography. Cardiac sympathetic activity is assessed by spectral analysis of heart rate variability on conscious rats (Etisense). Ultimately, hearts are withdrawn for cardiomyocyte isolation and calcium transient analysis, for assessment of calcium and adrenergic signalling pathways (western blot) and for histological analysis of fibrosis (Sirius red), hypertrophy (WGA) and cardiac sympathetic innervation (Tyrosine-hydroxylase staining). Results CSD prevents the IH-induced blunted cardiomyocyte response to isoproterenol challenge (ISO). ISO-induced cardiomyocyte shortening is about 78% on MI-N group, reduced to 28% in MI-IH and restored to 125% in MI-IH-CSD. Preliminary results on cardiac function indicate that CSD also improve long-term ejection fraction in MI-IH rats. Biochemical and histological analysis are on-going. Conclusion These results suggest that IH-induced sympathetic activity is responsible for adrenergic reserve depletion in our rat model of ischemic cardiomyopathy. Ongoing experiments will confirm if CSD also limits the IH-induced cardiac remodeling and contractile dysfunction.
- Published
- 2020
19. Transcription factor dimerization activates the p300 acetyltransferase
- Author
-
Srinivasan Rengachari, Esther Ortega, Naghmeh Hoghoughi, Saadi Khochbin, Daniel Panne, Alex S. Holehouse, Ziad Ibrahim, Jonathan Gaucher, Khochbin, Saadi, European Molecular Biology Laboratory [Grenoble] (EMBL), Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen], Max-Planck-Gesellschaft, University of Leicester, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), HP2 : Hypoxie et physiopathologies cardiovasculaires et respiratoires., Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Grenoble , Centre Hospitalier Universitaire de Grenoble, France-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Washington University in Saint Louis (WUSTL), and CHU de Grenoble , Centre Hospitalier Universitaire de Grenoble, France-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
- Subjects
0301 basic medicine ,Models, Molecular ,Transcription, Genetic ,[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Crystallography, X-Ray ,Ligands ,CBP ,Article ,03 medical and health sciences ,STAT1 ,Protein Domains ,Transcription (biology) ,Catalytic Domain ,Gene expression ,Humans ,p300-CBP Transcription Factors ,transcriptional regulation ,P300 ,Enhancer ,Transcription factor ,transcription factor ,ComputingMilieux_MISCELLANEOUS ,Regulation of gene expression ,Multidisciplinary ,biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Chemistry ,Lysine ,Acetylation ,Histone acetyltransferase ,IRF3 ,Chromatin ,Cell biology ,Enzyme Activation ,030104 developmental biology ,STAT1 Transcription Factor ,acetyltransferase ,biology.protein ,Interferon Regulatory Factor-3 ,Protein Multimerization ,Transcription Factors - Abstract
The transcriptional co-activator p300 is a histone acetyltransferase (HAT) that is typically recruited to transcriptional enhancers and regulates gene expression by acetylating chromatin. Here we show that the activation of p300 directly depends on the activation and oligomerization status of transcription factor ligands. Using two model transcription factors, IRF3 and STAT1, we demonstrate that transcription factor dimerization enables the trans-autoacetylation of p300 in a highly conserved and intrinsically disordered autoinhibitory lysine-rich loop, resulting in p300 activation. We describe a crystal structure of p300 in which the autoinhibitory loop invades the active site of a neighbouring HAT domain, revealing a snapshot of a trans-autoacetylation reaction intermediate. Substrate access to the active site involves the rearrangement of an autoinhibitory RING domain. Our data explain how cellular signalling and the activation and dimerization of transcription factors control the activation of p300, and therefore explain why gene transcription is associated with chromatin acetylation.
- Published
- 2018
20. From meiosis to postmeiotic events: The secrets of histone disappearance
- Author
-
Emilie Montellier, Saadi Khochbin, Sophie Rousseaux, Jonathan Gaucher, Nicolas Reynoird, and Fayçal Boussouar
- Subjects
Genetics ,biology ,Cell Biology ,Biochemistry ,Chromatin ,Cell biology ,Histone ,Histone H1 ,Histone methyltransferase ,Histone methylation ,Histone H2A ,biology.protein ,Histone code ,Nucleosome ,Molecular Biology - Abstract
One of the most obscure phenomena in modern biology is the near genome-wide displacement of histones that occurs during the postmeiotic phases of spermatogenesis in many species. Here we review the literature to show that, during spermatogenic differentiation, three major molecular mechanisms come together to 'prepare' the nucleosomes for facilitated disassembly and histone removal.
- Published
- 2009
21. Spermiogenèse : l’acétylation des histones déclenche la reprogrammation du génome mâle
- Author
-
Hervé Lejeune, Sandrine Curtet, Jean-Pierre Siffroi, Célia Ravel, Sophie Rousseaux, C. Derobertis, C. Jimenez, Cécile Caron, Anne-Laure Vitte, I. Aknin-Seifer, J. Thevenon, Rachel Levy, Jonathan Gaucher, Saadi Khochbin, A. K. Faure, K. Mc Elreavey, and Sylviane Hennebicq
- Subjects
Mutation ,Obstetrics and Gynecology ,General Medicine ,Biology ,medicine.disease_cause ,Genome ,Bromodomain ,Chromatin ,Cell biology ,chemistry.chemical_compound ,Histone ,Reproductive Medicine ,chemistry ,medicine ,biology.protein ,Epigenetics ,Reprogramming ,DNA - Abstract
During their post-meiotic maturation, male germ cells undergo an extensive reorganization of their genome, during which histones become globally hyperacetylated, are then removed and progressively replaced by transition proteins and finally by protamines. The latter are known to tightly associate with DNA in the mature sperm cell. Although this is a highly conserved and fundamental biological process, which is a necessary prerequisite for the transmission of the male genome to the next generation, its molecular basis remains mostly unknown. We have identified several key factors involved in this process, and their detailed functional study has enabled us to propose the first model describing molecular mechanisms involved in post-meiotic male genome reprogramming. One of them, Bromodomain Testis Specific (BRDT), has been the focus of particular attention since it possesses the unique ability to specifically induce a dramatic compaction of acetylated chromatin. Interestingly, a mutation was found homozygous in infertile men which, according to our structural and functional studies, disrupts the function of the protein. A combination of molecular structural and genetic approaches has led to a comprehensive understanding of new major actors involved in the male genome reprogramming and transmission.
- Published
- 2009
22. L’intrusion des régulateurs de l’épigénome mâle dans les cellules somatiques cancéreuses
- Author
-
Nicolas Reynoird, Jonathan Gaucher, Sophie Rousseaux, and Saadi Khochbin
- Subjects
Tumor cells ,General Medicine ,Biology ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology - Abstract
Dans les cellules saines, un ensemble de mecanismes dits « epigenetiques » assure une differenciation structurale et fonctionnelle du genome, necessaire au silence transcriptionnel de la majorite du genome et a l’activite de genes specifiques de differents tissus. La transformation oncogenique des cellules compromet la coherence de cette organisation et induit des repressions et activations aberrantes de genes. Alors que le silence transcriptionnel de certains regulateurs cellulaires critiques contribue clairement a la transformation maligne des cellules, le role oncogene de l’activation illegitime des genes tissu-specifiques dans les cellules cancereuses et pre-cancereuses reste peu etudie. Cet article vise (1) a demontrer le potentiel oncogene de l’expression illegitime, dans les cellules somatiques, de genes normalement exclusivement exprimes dans les cellules germinales mâles, dont les produits sont connus sous le nom de facteurs testiculaires du cancer ou C/T, notamment ceux modelant l’epigenome de ces cellules, et (2) a souligner leur interet en tant que marqueurs de l’etat cancereux et cibles therapeutiques prometteuses.
- Published
- 2008
23. Proteomic strategy for the identification of critical actors in reorganization of the post-meiotic male genome
- Author
-
Alexandra Debernardi, Jonathan Gaucher, Jérôme Garin, Sophie Rousseaux, Myriam Ferro, Saadi Khochbin, Jérôme Govin, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Etude de la dynamique des protéomes (EDyP ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Département Santé (DSANTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'étude de la dynamique des protéomes (LEDyP), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes (UGA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), and FERRO, Myriam
- Subjects
Male ,Proteomics ,Embryology ,Chromosomal Proteins, Non-Histone ,Gene regulatory network ,Haploidy ,Biology ,Genome ,Histones ,03 medical and health sciences ,Meiosis ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,DNA Packaging ,Genetics ,Animals ,Humans ,Nucleosome ,Gene Regulatory Networks ,Spermatogenesis ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Genomic organization ,0303 health sciences ,030302 biochemistry & molecular biology ,Nuclear Proteins ,Obstetrics and Gynecology ,Cell Biology ,Germ Cells ,Reproductive Medicine ,Proteome ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Ploidy ,Reprogramming ,Molecular Chaperones ,Developmental Biology - Abstract
After meiosis, during the final stages of spermatogenesis, the haploid male genome undergoes major structural changes, resulting in a shift from a nucleosome-based genome organization to the sperm-specific, highly compacted nucleoprotamine structure. Recent data support the idea that region-specific programming of the haploid male genome is of high importance for the post-fertilization events and for successful embryo development. Although these events constitute a unique and essential step in reproduction, the mechanisms by which they occur have remained completely obscure and the factors involved have mostly remained uncharacterized. Here, we sought a strategy to significantly increase our understanding of proteins controlling the haploid male genome reprogramming, based on the identification of proteins in two specific pools: those with the potential to bind nucleic acids (basic proteins) and proteins capable of binding basic proteins (acidic proteins). For the identification of acidic proteins, we developed an approach involving a transition-protein (TP)-based chromatography, which has the advantage of retaining not only acidic proteins due to the charge interactions, but also potential TP-interacting factors. A second strategy, based on an in-depth bioinformatic analysis of the identified proteins, was then applied to pinpoint within the lists obtained, male germ cells expressed factors relevant to the post-meiotic genome organization. This approach reveals a functional network of DNA-packaging proteins and their putative chaperones and sheds a new light on the way the critical transitions in genome organizations could take place. This work also points to a new area of research in male infertility and sperm quality assessments.
- Published
- 2012
24. Bromodomain-dependent stage-specific male genome programming by Brdt: Brdt: a master regulator of spermatogenesis
- Author
-
Hélène Holota, Debra J. Wolgemuth, Fabrice Lopez, Matthieu Gérard, Sandrine Curtet, Jean Imbert, Sophie Rousseaux, Patrick Héry, Thierry Buchou, Karin Pernet, Sylvie Jounier, Sarah Bertrand, Emilie Montellier, Alexandra Debernardi, Philippe Guardiola, Jonathan Gaucher, Fayçal Boussouar, Arnaud Depaux, Anne-Laure Vitte, Saadi Khochbin, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, SNP, Transcriptome & Epigénomique [CHU Angers] (Plateforme STE), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Columbia University Medical Center (CUMC), Columbia University [New York], Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Genetics ,0303 health sciences ,BRD4 ,General Immunology and Microbiology ,biology ,General Neuroscience ,[SDV]Life Sciences [q-bio] ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Bromodomain ,Gene expression profiling ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Histone ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Molecular Biology ,Gene ,Germ cell ,030304 developmental biology - Abstract
International audience; Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic and post-meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential genes and repressing a ‘progenitor cells’ gene expression program. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for Brdt's first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome.
- Published
- 2012
25. Molecular models for post-meiotic male genome reprogramming
- Author
-
Anne-Laure Vitte, Emilie Montellier, Jonathan Gaucher, Fayçal Boussouar, Saadi Khochbin, Sandrine Curtet, Sophie Rousseaux, and Nicolas Reynoird
- Subjects
Genetics ,Male ,Genome ,biology ,Urology ,Nuclear Proteins ,Context (language use) ,Acetylation ,Computational biology ,Models, Biological ,Chromatin ,Histones ,Meiosis ,Histone ,Reproductive Medicine ,biology.protein ,Histone code ,Animals ,Humans ,Epigenetics ,Reprogramming - Abstract
The molecular basis of post-meiotic male genome reorganization and compaction constitutes one of the last black boxes in modern biology. Although the successive transitions in DNA packaging have been well described, the molecular factors driving these near genome-wide reorganizations remain obscure. We have used a combination of different approaches aiming at the discovery of critical factors capable of directing the post-meiotic male genome reprogramming, which is now shedding new light on the nature of the fundamental mechanisms controlling post-meiotic histone replacement and genome compaction. Here we present a summary of these findings. The identification of the first factor capable of reading a precise combination of histone acetylation marks, BRDT, allowed highlighting a critical role for the genome-wide histone hyperacetylation that occurs before generalized histone replacement. In this context, the recent identification of a group of new histone variants capable of forming novel DNA packaging structures on specific regions during late spermatogenesis, when hyperacetylated histones are massively replaced in spermatids, also revealed the occurrence of a post-meiotic region-specific genome reprogramming. Additionally, the functional characterization of other molecular actors and chaperones in action in post-meiotic cells now allows one to describe the first general traits of the mechanisms underlying the structural transitions taking place during the post-meiotic reorganization and epigenetic reprogramming of the male genome.
- Published
- 2011
26. Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis
- Author
-
Sophie Rousseaux, Jean Dorsey, Shelley L. Berger, Saadi Khochbin, Jonathan Gaucher, and Jérôme Govin
- Subjects
Male ,Histone-modifying enzymes ,Saccharomyces cerevisiae Proteins ,Saccharomyces cerevisiae ,DNA Mutational Analysis ,Gametogenesis ,Histones ,Mice ,Genetics ,Nucleosome ,Animals ,Epigenetics ,Spermatogenesis ,biology ,biology.organism_classification ,Chromatin Assembly and Disassembly ,Immunohistochemistry ,Bromodomain ,Chromatin ,Nucleosomes ,Histone ,Acetylation ,Mutation ,biology.protein ,Developmental Biology ,Research Paper - Abstract
Profound epigenetic differences exist between genomes derived from male and female gametes; however, the nature of these changes remains largely unknown. We undertook a systematic investigation of chromatin reorganization during gametogenesis, using the model eukaryote Saccharomyces cerevisiae to examine sporulation, which has strong similarities with higher eukaryotic spermatogenesis. We established a mutational screen of histones H3 and H4 to uncover substitutions that reduce sporulation efficiency. We discovered two patches of residues—one on H3 and a second on H4—that are crucial for sporulation but not critical for mitotic growth, and likely comprise interactive nucleosomal surfaces. Furthermore, we identified novel histone post-translational modifications that mark the chromatin reorganization process during sporulation. First, phosphorylation of H3T11 appears to be a key modification during meiosis, and requires the meiotic-specific kinase Mek1. Second, H4 undergoes amino tail acetylation at Lys 5, Lys 8, and Lys 12, and these are synergistically important for post-meiotic chromatin compaction, occurring subsequent to the post-meiotic transient peak in phosphorylation at H4S1, and crucial for recruitment of Bdf1, a bromodomain protein, to chromatin in mature spores. Strikingly, the presence and temporal succession of the new H3 and H4 modifications are detected during mouse spermatogenesis, indicating that they are conserved through evolution. Thus, our results show that investigation of gametogenesis in yeast provides novel insights into chromatin dynamics, which are potentially relevant to epigenetic modulation of the mammalian process.
- Published
- 2010
27. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain
- Author
-
Ulrich Steuerwald, Darren J. Hart, Christoph W. Müller, Anne-Laure Vitte, Montserrat Soler-López, Jérôme Govin, Jonathan Gaucher, Karin Sadoul, Sophie Rousseaux, Jeroen Krijgsveld, Jeanne Morinière, Saadi Khochbin, Sandrine Curtet, Carlo Petosa, Laboratoire européen de biologie moléculaire - European Molecular Biology Laboratory (EMBL Grenoble), European Molecular Biology Laboratory [Grenoble] (EMBL), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), European Molecular Biology Laboratory [Heidelberg] (EMBL), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
Models, Molecular ,Protein Conformation ,[SDV]Life Sciences [q-bio] ,Biology ,Crystallography, X-Ray ,Substrate Specificity ,Histone H4 ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Histone H1 ,Allosteric Regulation ,Histone H2A ,Chlorocebus aethiops ,Histone code ,Animals ,Histone octamer ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Binding Sites ,Lysine ,Nuclear Proteins ,Acetylation ,Chromatin ,Cell biology ,Bromodomain ,Protein Structure, Tertiary ,Histone ,Biochemistry ,030220 oncology & carcinogenesis ,Histone methyltransferase ,COS Cells ,biology.protein ,Protein Binding - Abstract
Letter; International audience; A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family1, 2. Whereas effector-mediated recognition of single post-translational modifications is well characterized3, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules4. For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark5. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family6. Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm7, 8, 9, 10. Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope
- Published
- 2009
28. [Intrusion of male epigenome regulators in somatic cancer cells]
- Author
-
Sophie, Rousseaux, Nicolas, Reynoird, Jonathan, Gaucher, and Saadi, Khochbin
- Subjects
Male ,Cell Transformation, Neoplastic ,Neoplasms ,Testis ,Humans ,DNA Methylation ,Spermatogenesis ,Epigenesis, Genetic - Abstract
In healthy cells, several epigenetic mechanisms ensure structural and functional differentiation of the genome, and are necessary for the transcriptional silencing of most of the genome while a few genes, specific for each tissue type, are activated. Cell transformation disturbs this organization and induces the aberrant repression or activation of many genes. Whereas the transcriptional silencing of some critical cell regulators clearly contributes to cell malignant transformation, the oncogenic role of the illegitimate activation of tissue-specific genes in cancerous and pre-cancerous cells is still poorly known. This review aims to demonstrate the oncogenic potential of the illegitimate expression, in somatic cells, of genes, whose expression is normally restricted to male germ cells, encoding factors known as cancer testis or C/T, and particularly those involved in re-organizing the epigenome in these cells. The value of these genes, and of the factors they encode, in terms of cancer markers and promissing therapeutic targets will also be stressed.
- Published
- 2008
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.