Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

EVALUATION OF OBSTRUCTIVE SLEEP APNEA SYNDROME AS A RISK FACTOR FOR DIABETIC MACULAR EDEMA IN PATIENTS WITH TYPE II DIABETES.

PURPOSE: To evaluate the association between obstructive sleep apnea and diabetic macular edema (DME) in patients with Type II diabetes, using the apnea-hypopnea index and other nocturnal hypoxemia parameters. METHODS: This cross-sectional, case-control study included 99 patients with Type II diabetes: the first group included patients with DME (DME+ group) and the second patients without DME (DME- group). Polysomnography was performed in all patients. The two groups were compared, and the risk factors were studied using logistic regression. RESULTS: The DME+ group comprised 38 patients, and the DME- group comprised 61 patients, aged a mean 68.8 years and 66.3 years (P = 0.27), respectively; mean body mass index was 29.7 and 30.9 (P = 0.16), respectively. The mean apnea-hypopnea index was significantly higher in the DME+ group (43.95 [13.5-87.3]) than in the DME- group (35.18 [3.55-90.7]) (P = 0.034). Patients with DME had more severe obstructive sleep apnea (apnea-hypopnea index >30) than the others: 71% versus 50.8% (P = 0.049). Cumulative time of SPO2 below 90% (CT90%) was independently associated with DME after adjusting for confounding factors, whereas there was no difference between the oxygen desaturation index and minimum O2 saturation. CONCLUSION: Severe obstructive sleep apnea (apnea-hypopnea index >30) and parameters of nocturnal hypoxemia (cumulative time of SPO2 below 90%) are associated with DME.

A French update on the Self-Efficacy Measure for Sleep Apnea (SEMSA) to assess continuous positive airway pressure (CPAP) use.

PURPOSE: The Self-Efficacy Measure for Sleep Apnea (SEMSA) is a 26-item self-questionnaire composed of three factors: risk perception of obstructive sleep apnea syndrome (OSAS), benefit of continuous positive airway pressure (CPAP), and self-efficacy (the confidence to engage in CPAP use). It is used to evaluate health beliefs about OSAS and CPAP in order to optimize CPAP use. The purpose of this study was to design and validate a French version of the SEMSA. METHODS: A forward-backward translation of the SEMSA was performed. Subjects with OSAS treated by CPAP and followed by our sleep clinic were invited to complete the questionnaire. The psychometric properties of the French SEMSA version were analyzed in terms of its construct validity (with confirmatory factor analysis, CFA), internal structural validity (Cronbach's alpha coefficient), and external validity (Pearson's correlation between SEMSA score and duration of CPAP use). RESULTS: Two hundred eighty-eight subjects filled in the questionnaire. The mean age was 63.16 ± 12.73 years. The number of years since the beginning of CPAP treatment was 6.58 ± 6.03 years. The mean CPAP use duration was 6.19 ± 2.03 h/night. CFA was unsatisfactory (RMSEA = 0.066 and CFI = 0.88). The exploratory factor analysis revealed a fourth factor named "cardiovascular risk" factor. Cronbach's alpha coefficient was 0.886. The correlation between the "self-efficacy" factor and the duration of CPAP use was significant (r = 0.26, p ≤ 0.001). CONCLUSIONS: The French version of the SEMSA is a psychometrically acceptable self-report questionnaire for measuring health beliefs and behavior in French patients with OSAS treated with CPAP. Such translation and validation should lead to the adoption of validated psychosocial methods for improving CPAP use.

Sex differences in mandibular repositioning device therapy effectiveness in patients with obstructive sleep apnea syndrome.

PURPOSE: Mandibular repositioning devices (MRDs) are an effective treatment option for obstructive sleep apnea syndrome (OSAS), particularly in patients who refuse or cannot tolerate continuous positive airway pressure (CPAP). However, sex differences in the response to therapy and predictors of response are not clearly defined. This analysis of data from the long-term prospective ORCADES trial compared MRD efficacy in men and women with OSAS. METHODS: The ORCADES study included patients with newly diagnosed mild-to-moderate or severe OSAS who refused or were non-compliant with CPAP. MRD therapy was titrated over 3-6 months. The primary endpoint was treatment success (≥ 50% decrease in apnea-hypopnea index (AHI)). Complete response was defined using a range of AHI cut-off values (< 5/h, < 10/h, < 15/h). RESULTS: Overall treatment success rates were 89% in women and 76% in men (p = 0.019); corresponding rates in those with severe OSAS (AHI > 30/h) were 100% and 68% (p = 0.0015). In women vs. men, overall complete response rates at AHI cut-off values of < 5/h, <10/h, and < 15/h were 49 vs. 34% (p = 0.0052), 78 vs. 62% (p = 0.016), and 92 vs. 76% (p = 0.0032). On multivariate analysis, significant predictors of MRD treatment success were overbite and baseline apnea index in men, and neck circumference and no previous CPAP therapy in women. There were sex differences in the occurrence of side effects. Temporomandibular joint pain was the most common reason for stopping MRD therapy. CONCLUSIONS: MRD therapy was effective in women with OSA of any severity, with significantly higher response rates compared with men especially in severe OSAS. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01326143).

The "great live and move challenge": a program to promote physical activity among children aged 7-11 years. Design and implementation of a cluster-randomized controlled trial.

BACKGROUND: Recent population-based surveys have reported that large majorities of children in France, Europe and in the US are not complying with international physical activity (PA) guidelines. There is, therefore, a need to find programs that will improve children's PA habits from an early age. Theory-based interventions that include school, family, and community involvement have the potential to generate a considerable increase in the PA level of children. The theory of planned behavior (TPB) is one of the most widely tested models of the factors influencing health-related behaviors. The Great Live and Move Challenge (GLMC) is an extended TPB-based intervention designed to promote PA in French primary school children aged 7-11 years. The objective of this paper is to describe the protocol of a randomized controlled trial to evaluate the effectiveness of the GLMC on the PA level of children. METHODS: This is a two-year cluster-randomized controlled trial comparing an intervention group to a control group, randomized into clusters (community of communes) and stratified by department (Hérault, Gard, Aude) and residential environment (urban, rural). The goal is to recruit 4000 children. The GLMC involves children and their parents, and multiple local grassroots partners, such as school teachers, municipal officials and policy stakeholders. The intervention will be delivered over 3.5 months per year for a two-year period. Pre- and post-intervention, children and parents will be asked to fulfill a questionnaire concerning current PA level, TPB variables (i.e., intentions, attitudes, subjective norms, perceived behavioral control) and other psychosocial variables (e.g., perceptions of activity opportunities). A subsample of 400 children will be proposed to wear an accelerometer (i.e., the Actigraph GT3X+). The primary hypothesis is that the GLMC intervention will increase the proportion of children achieving the World Health Organization's recommended 60 min of moderate to vigorous PA per day by 15%. DISCUSSION: This study will evaluate the effectiveness of a multilevel, theory-based PA program and potentially provide valuable information for schools and public health officers looking for innovative PA programs. TRIAL REGISTRATION: ISRCTN:61116221 , 19/06/2018.

Sleep disorders in obese children are not limited to obstructive sleep apnoea syndrome.

AIM: This study was to characterise respiratory and nonrespiratory sleep disorders in obese children and evaluate the diagnostic and therapeutic impact of a specific sleep consultation. METHODS: A descriptive study was conducted in obese French children who received multidisciplinary care management from the hospital centre for paediatric obesity in Bordeaux. This followed a specific sleep consultation between 2007 and 2015, because their paediatrician had identified symptoms suggestive of sleep disorders. RESULTS: The sleep specialist confirmed the presence of a sleep disorder in 98.4% of the 128 obese children, with a mean age of 12.1 ± 3.2 years. These included respiratory sleep disorders, hypersomnolence, insomnia and circadian rhythm sleep-wake disorders. Polysomnography revealed that 46.1% had respiratory sleep disorders and 24.2% had obstructive sleep apnoea syndrome (OSAS). Just under half (47.6%) were referred to an otorhinolaryngologist for sleep care management, 30.5% were referred to an orthodontist, 17.9% had melatonin treatment and 13.3% received continuous positive airway pressure ventilation. CONCLUSION: Sleep disorders in obese children were not limited to respiratory sleep disorders including OSAS. A systematic specific consultation with a sleep specialist is essential for the diagnosis and care of such children and would be beneficial when treating paediatric obesity.

Impact and Moderating Variables of an Intervention Promoting Physical Activity Among Children: Results From a Pilot Study.

This pilot study pursued three objectives: to assess the effect of a 1-month multilevel intervention on the PA of children, to assess the impact of the intervention on the theory of planned behavior (TPB) variables, and to evaluate the extent to which the impact of the intervention on PA and TPB variables varied according to personal (i.e., gender and age) and situational (i.e., class and school) moderating variables. Children were aged 7 to 11 years ( n = 306). Analyses revealed a significant increase of PA practice and TPB variables ( ps < .001). Age (i.e., being a younger child) was associated with a higher increase on attitude and perceived control ( ps < .01). The class or the school levels explained a meaningful variance in the evolution of PA or TPB variables (intraclass correlation coefficients > .10). The present study reports the interest and feasibility of a multilevel intervention to increase PA and TPB variables in children.

Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets.

OBJECTIVE: Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6α-ethyl-chenodeoxycholic acid, modulate platelet activation nongenomically. APPROACH AND RESULTS: FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin αIIbß3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. CONCLUSIONS: This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease.

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

BACKGROUND: Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). OBJECTIVE: We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. METHODS: Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. RESULTS: HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and TH2 and TH17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1ß levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including TH2 and TH17 infiltration. CONCLUSION: These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s.

Promoting Physical Activity among Children: The "Great Live and Move Challenge" / Promouvoir l'activité physique des enfants : Le « Grand Défi Vivez Bougez ¼.

Objective: The "Great Live and Move Challenge" (GLMC) is an intervention designed to promote physical activity (PA) in schools and the community among 6- to 11-year-old schoolchildren and their families.Method: This project, implemented in the Montpellier and Pays Coeur d'Hérault regions since 2013, encourages children to quantify their daily PA level by illustrating each 15 minutes of exercise by an "energy cube". Based on collaboration between pilots, teachers and policymakers, this project is implemented over a 6-week period in schools, municipalities and recreation centres. "Great Challenge" events are organized to promote PA. The GLMC is also a theory-based intervention based on the tenets of the planned behaviour theory.Results: Since the 2014-2015 edition, 2,243 children have taken part in the GLMC and have accumulated 391,102 "energy cubes". In addition, more than 30 "Great Challenge" events have been organized. Since its launch during the 2012-2013 school year, the numbers of children who have taken part in the GLMC have been multiplied by 5.58. The mean number of daily "energy cubes" accumulated by children has increased from 4.04 in the first year to 6.22 in 2014-2015.Conclusion: The "energy cube" can provide a measure of the commitment of children and their surrounding community in a comprehensive approach to PA promotion.

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.

[Sorting of senescent cells by flow cytometry: Specificities and pitfalls to avoid]. / Tri des cellules sénescentes par cytométrie en flux - Des spécificitéset des pièges à éviter.

Cells can be reprogrammed into senescence to adapt to a variety of stresses, most often affecting the genome integrity. Senescent cells accumulate with age or upon various insults in almost all tissues, and contribute to the development of several age-associated pathologies. Studying the molecular pathways involved in senescence induction, maintenance, or escape is challenged by the heterogeneity in the level of commitment to senescence, and by the pollution of senescent cell populations by proliferating pre- or post-senescent cells. We coped with these difficulties by developing a protocol for sorting senescent cells by flow cytometry, based on three major senescence markers : the SA-ß-Galactosidase activity, the size of the cells, and their granularity reflecting the accumulation of aggregates, lysosomes, and altered mitochondria. We address the issues related to sorting senescent cells, the pitfalls to avoid, and propose solutions for sorting viable cells expressing senescent markers at different extents.

Title: Tri des cellules sénescentes par cytométrie en flux - Des spécificitéset des pièges à éviter. Abstract: La sénescence est un état d'adaptation des cellules au stress qui contribue au vieillissement et au développement de nombreuses maladies. Étudier les voies moléculaires modulant l'induction, le maintien ou l'échappement de la sénescence est compliqué par la contamination des populations de cellules sénescentes par des cellules proliférantes pré- ou post-sénescentes. Pour contourner cette difficulté, nous avons développé un protocole de tri par cytométrie en flux, fondé sur trois marqueurs majeurs de sénescence (l'activité SA-ß-galactosidase, la taille et la granularité des cellules), qui permet de trier des cellules sénescentes viables, à des degrés choisis d'engagement dans le phénotype.

O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts.

Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked ß-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice.

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber-DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic-hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

Flow Cytometry-based Method for Efficient Sorting of Senescent Cells.

Cellular senescence is a reprogrammed cell state triggered as an adaptative response to a variety of stresses, most often those affecting the genome integrity. Senescent cells accumulate in most tissues with age and contribute to the development of several pathologies. Studying molecular pathways involved in senescence induction and maintenance, or in senescence escape, can be hindered by the heterogeneity of senescent cell populations. Here, we describe a flow cytometry strategy for sorting senescent cells according to three senescence canonical markers whose thresholds can be independently adapted to be more or less stringent: (i) the senescence-associated-ß-galactosidase (SA-ß-Gal) activity, detected using 5-dodecanoylaminofluorescein Di-ß-D-galactopyranoside (C12FDG), a fluorigenic substrate of ß-galactosidase; (ii) cell size, proportional to the forward scatter value, since increased size is one of the major changes observed in senescent cells; and (iii) cell granularity, proportional to the side scatter value, which reflects the accumulation of aggregates, lysosomes, and altered mitochondria in senescent cells. We applied this protocol to the sorting of normal human fibroblasts at the replicative senescence plateau. We highlighted the challenge of sorting these senescent cells because of their large sizes, and established that it requires using sorters equipped with a nozzle of an unusually large diameter: at least 200 µm. We present evidence of the sorting efficiency and sorted cell viability, as well as of the senescent nature of the sorted cells, confirmed by the detection of other senescence markers, including the expression of the CKI p21 and the presence of 53BP1 DNA damage foci. Our protocol makes it possible, for the first time, to sort senescent cells from contaminating proliferating cells and, at the same time, to sort subpopulations of senescent cells featuring senescent markers to different extents. Graphical abstract.

A time- and space-resolved nuclear receptor atlas in mouse liver.

The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.

Pharmacological HDAC inhibition impairs pancreatic ß-cell function through an epigenome-wide reprogramming.

Histone deacetylases enzymes (HDACs) are chromatin modifiers that regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic ß cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic ß-cell identity and function using the pan-HDAC inhibitor trichostatin A through chromatin immunoprecipitation assays and RNA sequencing experiments. We observed that TSA alters insulin secretion associated with ß-cell specific transcriptome programming in both mouse and human ß-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative ß-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that HDAC activity could be required to protect against loss of ß-cell identity with unsuitable expression of genes associated with alternative cell fates.