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.
Subject(s)
Protein Multimerization , Transcription Factors/chemistry , Transcription Factors/metabolism , p300-CBP Transcription Factors/chemistry , p300-CBP Transcription Factors/metabolism , Acetylation , Catalytic Domain , Chromatin/chemistry , Chromatin/metabolism , Crystallography, X-Ray , Enzyme Activation , Humans , Interferon Regulatory Factor-3/chemistry , Interferon Regulatory Factor-3/metabolism , Ligands , Lysine/chemistry , Lysine/metabolism , Models, Molecular , Protein Domains , STAT1 Transcription Factor/chemistry , STAT1 Transcription Factor/metabolism , Transcription, GeneticABSTRACT
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.
Subject(s)
Butyrates/metabolism , Epigenesis, Genetic , Gene Expression Regulation, Developmental , Histones/metabolism , Nuclear Proteins/genetics , Promoter Regions, Genetic , Protein Processing, Post-Translational , Spermatocytes/metabolism , Acetylation , Animals , Binding Sites , Cell Differentiation , Chromatin Assembly and Disassembly , Genome-Wide Association Study , Histones/chemistry , Histones/genetics , Lysine , Male , Mice , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Protein Conformation , Structure-Activity Relationship , Transcription, Genetic , Transcriptional ActivationABSTRACT
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.
Subject(s)
Alcohol Drinking/metabolism , Circadian Rhythm , Ethanol/metabolism , Liver/metabolism , Alcohol Drinking/genetics , Animals , Humans , Male , Mice, Inbred C57BL , Sterol Regulatory Element Binding Proteins/genetics , Sterol Regulatory Element Binding Proteins/metabolism , TranscriptomeABSTRACT
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.
Subject(s)
Vascular Diseases , Williams Syndrome , Humans , Mice , Male , Female , Animals , Elastin/metabolism , Elastic Tissue/metabolism , Haploinsufficiency , Aorta/metabolism , Vascular Diseases/pathologyABSTRACT
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: The interplay between metabolism and epigenetics and its molecular characterization in cancer cells identifies potential targets for the development of new therapies.
Subject(s)
Neoplasms/genetics , Neoplasms/metabolism , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Epigenesis, Genetic , HumansABSTRACT
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.
Subject(s)
Gametogenesis/genetics , Histones/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Animals , Chromatin Assembly and Disassembly/genetics , DNA Mutational Analysis , Histones/genetics , Immunohistochemistry , Male , Mice , Mutation/genetics , Nucleosomes/chemistry , Nucleosomes/genetics , Saccharomyces cerevisiae Proteins/genetics , SpermatogenesisABSTRACT
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.
Subject(s)
Nuclear Proteins/metabolism , Spermatogenesis/physiology , Animals , Gene Expression Profiling , Genome/physiology , Histone Acetyltransferases/metabolism , Histones/metabolism , Male , Meiosis/physiology , Mice , Spermatozoa/growth & development , Spermatozoa/metabolismABSTRACT
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 family. Whereas effector-mediated recognition of single post-translational modifications is well characterized, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules. 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 mark. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family. 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 sperm. 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.
Subject(s)
Histones/chemistry , Histones/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Acetylation , Allosteric Regulation , Animals , Binding Sites , COS Cells , Chlorocebus aethiops , Chromatin/chemistry , Chromatin/metabolism , Crystallography, X-Ray , Lysine/metabolism , Mice , Models, Molecular , Nuclear Proteins/genetics , Protein Binding , Protein Conformation , Protein Structure, Tertiary , Substrate SpecificityABSTRACT
In a prospective cohort of OSA patients without comorbidities at inclusion, age, mean blood pressure, mean oxygen saturation and minimum oxygen saturation were associated with long-term incidence of severe health events https://bit.ly/3VyYEzC.
ABSTRACT
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.
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.
Subject(s)
Genome , Meiosis/physiology , Proteomics/methods , Animals , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , DNA Packaging , Gene Regulatory Networks , Germ Cells/cytology , Germ Cells/physiology , Haploidy , Histones/genetics , Histones/metabolism , Humans , Male , Molecular Chaperones/genetics , Molecular Chaperones/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Spermatogenesis/physiologyABSTRACT
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.
Subject(s)
Hypoxia , Transcriptome , Altitude , Humans , Hypoxia/genetics , Transcriptome/geneticsABSTRACT
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.
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.
Subject(s)
COVID-19 , Sleep, REM , Communicable Disease Control , Humans , Pandemics , SARS-CoV-2 , SleepABSTRACT
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 <0.01) and male gender (p = 0.02). Concerning fibrosis, among 2218 patients 397 had fibrosis (18%). Risk factors associated with fibrosis were BMI>26 kg/m2, age, male gender, and type 2 diabetes (all p-values <0.01). AHI severity was not associated with fibrosis. A combination of AHI >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.
Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Pulmonary Disease, Chronic Obstructive , Sleep Apnea, Obstructive , Humans , Male , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Polysomnography , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/epidemiology , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/epidemiologyABSTRACT
Chronic intermittent hypoxia (CIH) occurring during sleep apnea amplifies infarct size owing to ischemia-reperfusion. CIH activates hypoxia-inducible factor 1 (HIF-1) and activating transcription factor 4 (ATF4). However, whether HIF-1 and ATF4 interact to promote cardiomyocyte death remains unexplored. For the first time, we observed that in myocardium from apneic patients, CCAAT enhancer-binding protein homologous protein (CHOP) expression is increased and HIF-1α expression is correlated with sleep apnea severity. In mice, single-allele deletion of HIF-1α prevents CIH increase in CHOP expression and infarct size. We uncovered a physical interaction between HIF-1α and ATF4 in CIH that may represent a novel cardiomyocyte death complex.
Subject(s)
Activating Transcription Factor 4/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia , Myocardial Infarction , Sleep Apnea Syndromes , Animals , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Death , Humans , Hypoxia/complications , Hypoxia/etiology , Hypoxia/metabolism , Mice , Myocardial Infarction/etiology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/metabolismABSTRACT
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.
Subject(s)
Adenosylhomocysteinase , Chromatin Assembly and Disassembly , Circadian Clocks , Methionine , ARNTL Transcription Factors/genetics , Adenosylhomocysteinase/genetics , Adenosylhomocysteinase/metabolism , Animals , CLOCK Proteins , Chromatin , Circadian Rhythm/genetics , Methionine/metabolism , Mice , S-Adenosylhomocysteine/metabolismABSTRACT
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.
Subject(s)
Adipose Tissue/physiopathology , Adiposity , Sleep Apnea, Obstructive/physiopathology , Adipokines/metabolism , Adipose Tissue/metabolism , Animals , Cardiovascular System/metabolism , Cardiovascular System/physiopathology , Continuous Positive Airway Pressure , Energy Metabolism , Humans , Inflammation Mediators/metabolism , Lung/metabolism , Lung/physiopathology , Signal Transduction , Sleep Apnea, Obstructive/metabolism , Sleep Apnea, Obstructive/therapy , Treatment OutcomeABSTRACT
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.
Subject(s)
DNA Methylation/genetics , Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Epigenesis, Genetic/genetics , Humans , Male , Spermatogenesis/genetics , Testis/pathologyABSTRACT
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.