Resident macrophage-dependent immune cell scaffolds drive anti-bacterial defense in the peritoneal cavity.

Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omentum revealed that large peritoneal macrophages (LPMs) rapidly cleared bacteria and adhered to the mesothelium, forming multilayered cellular aggregates composed by sequentially recruited LPMs, B1 cells, neutrophils, and monocyte-derived cells (moCs). The formation of resident macrophage aggregates (resMφ-aggregates) required LPMs and thrombin-dependent fibrin polymerization. E. coli infection triggered LPM pyroptosis and release of inflammatory mediators. Resolution of these potentially inflammatory aggregates required LPM-mediated recruitment of moCs, which were essential for fibrinolysis-mediated resMφ-aggregate disaggregation and the prevention of peritoneal overt inflammation. Thus, resMφ-aggregates provide a physical scaffold that enables the efficient control of peritoneal infection, with implications for antimicrobial immunity in other body cavities, such as the pleural cavity or brain ventricles.

PGRMC2 is an intracellular haem chaperone critical for adipocyte function.

Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.

Discovery of small-molecule enzyme activators by activity-based protein profiling.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.

Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

The nuclear receptor LXR is a glucose sensor.

The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-alpha and LXR-beta. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.

Linking epigenetics to lipid metabolism: focus on histone deacetylases.

A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence-independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders.

Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

[Patient safety and the international goals: Consensus document]. / Consenso: seguridad del paciente y las metas internacionales.

Patient safety is one of the dimensions of care. Medical advances have made assistance processes more and more complex, and there is usually a combination of circumstances that converge for errors to occur. Adverse events constitute a serious public health problem, causing damages of varying degrees to the patient and his family, which also leads to an increase in the cost of the care process and hospital stay. Most of the adverse events occur in hospitals because their complexity is subject to a greater risk associated with care. That is why we present this consensus with the aim of offering tools whose implementation can contribute to provide a safer healthcare.

La seguridad del paciente es una de las dimensiones de la atención. Los avances médicos han tornado los procesos de atención cada vez más complejos, y, usualmente, hay una conjunción de circunstancias que confluyen para que ocurran errores. Los eventos adversos constituyen un problema grave de salud pública al ocasionar daños de diversos grados al paciente y a su familia, lo cual, además, lleva a incrementar el costo del proceso de atención y la estancia hospitalaria. La mayoría de los eventos adversos se producen en los hospitales, ya que, por su complejidad, su población está sometida a un mayor riesgo asociado a la atención. Se presenta este consenso con el objetivo de ofrecer herramientas cuya implementación contribuya a brindar una atención más segura.

Bile acids and gene regulation: from nuclear receptors to chromatin.

Transcription regulation by bile acids is far more complicated than it appeared at first when several groups began their investigations in the early '90. It has become clear now that bile acids regulate the transcription of genes involved in bile acid synthesis, transport and other metabolic pathways via multiple mechanisms that involve transcription factors, nuclear receptors, coregulators, chromatin and the related modifying enzyme complexes. At a first look this might seem surprising but if one considers the physical-chemical properties of these molecules it should be evident that, due to their detergent properties, bile acids may be harmful if they reach high concentrations in the liver and intestine. Therefore, living organisms have developed biochemical mechanisms that finely tune the concentration of bile acids according to the body needs and in response to environmental challenges. In this review, we will discuss the most recent evidences on the mechanisms through which bile acids regulate gene transcription, including the function of nuclear receptors and emphasizing the emerging role of chromatin and the associated modifying enzymes.

The pharmacological exploitation of cholesterol 7alpha-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodelling to reduce plasma cholesterol.

Mammals dispose of cholesterol mainly through 7alpha-hydroxylated bile acids, and the enzyme catalyzing the 7alpha-hydroxylation, cholesterol 7alpha-hydroxylase (CYP7A1), has a deep impact on cholesterol homeostasis. In this review, we present the study of regulation of CYP7A1 as a good exemplification of the extraordinary contribution of molecular biology to the advancement of our understanding of metabolic pathways that has taken place in the last 2 decades. Since the cloning of the gene from different species, experimental evidence has accumulated, indicating that the enzyme is mainly regulated at the transcriptional level and that bile acids are the most important physiological inhibitors of CYP7A1 transcription. Multiple mechanisms are involved in the control of CYP7A1 transcription and a variety of transcription factors and nuclear receptors participate in sophisticated regulatory networks. A higher order of transcriptional regulation, stemming from the so-called histone code, also applies to CYP7A1, and recent findings clearly indicate that chromatin remodelling events have profound effects on its expression. CYP7A1 also acts as a sensor of signals coming from the gut, thus representing another line of defence against the toxic effects of bile acids and a downstream target of agents acting at the intestinal level. From the pharmacological point of view, bile acid binding resins were the first primitive approach targeting the negative feed-back regulation of CYP7A1 to reduce plasma cholesterol. In recent years, new drugs have been designed based on recent discoveries of the regulatory network, thus confirming the position of CYP7A1 as a focus for innovative pharmacological intervention.

Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits.

OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.

[The current status of patient safety in Argentina: Cross sectional study]. / Diagnóstico de situación de seguridad del paciente en Argentina. Estudio transversal.

BACKGROUND: Patient safety is a priority for healthcare organizations. For the PRONAP´s 2013 final exam, the Quality & Patient Safety Subcommittee and the PRONAP managers designed a survey to be answered by pediatrician students nationwide. It was destined to evaluate attitudes, practices and safety conditions in which they worked. AIM: To assess the current state of practices in patient safety. MATERIAL AND METHODS: Setting and sample: PRONAP students (7,438 pediatrician nationwide) who answered 2013 final exam. Instrument: Patient Safety Survey about pediatric inpatient (9 domains) and outpatient (5 domains) practices, and population data. RESULTS: Patient Safety Survey: 6424 answered (86%). Population: age: 42% 30-40 years. Women: 80%. Residence in Pediatrics: 83%. Patient safety training: 30%. geographical origin: all provinces and CABA. Inpatient practices: 15% answered their institution had Patient Safety Committee. 74% of institutions did not have event reporting systems, 70% didn´t have a patient´s identification system. 32% answered that drug prescription should be done upon vademecum at their institution, and 27% had infection´s control programs, 28% performed surgical checklist in operating room and 55% had a standardized patient hand-off. Outpatient practices: 62% said they had washbasins, 56% had soap available, and 63% alcohol gel. 70% answered children with a supposed infectious rash did not wait his turn separately. CONCLUSION: This study shows that most pediatricians in Argentine work without prioritizing patient safety, both in ambulatory and inpatient practice.

Introducción. La seguridad de los pacientes es un objetivo prioritario de las organizaciones de salud. Objetivo. Conocer las actitudes, prácticas y condiciones de seguridad del paciente pediátrico en Argentina. Material y métodos. La Subcomisión de Calidad y Seguridad del Paciente de la Sociedad Argentina de Pediatría y Programa Nacional de Actualización Pediátrica elaboraron una encuesta sobre seguridad del paciente y prevención de errores (datos poblacionales, 9 dimensiones para internación, 5 para atención ambulatoria). El instrumento fue enviado a los alumnos de Programa Nacional de Actualización Pediátrica 2013, distribuidos en todo el país. Resultados. Encuesta administrada a 7438 alumnos; respondida por 6424 (86%). Población: edad: 42% de 30 a 40 años. Mujeres: 80%. Residencia/concurrencia en Pediatría: 83%. Formación en seguridad del paciente: 30%. Internación: 15% respondió que la institución donde trabajaba tenía Comité de Seguridad. El 74% carecía de sistemas de reporte de eventos; 70% no tenía identificación de pacientes; 32% debía prescribir según vademécum; 27% tenía programas de control de infecciones; 28% aplicaba la lista de verificación quirúrgica. Ambulatorio: 62% respondió que había lavatorios; 56%, que había jabón; y 63%, gel alcohólico disponible. El 70% contestó que los niños con enfermedades exantemáticas esperaban en lugares comunes. Conclusión. Este trabajo muestra que gran parte de los pediatras argentinos encuestados trabaja en condiciones en las que no se prioriza la seguridad del paciente, tanto en pediatría ambulatoria como de internación

The Influence of a KDT501, a Novel Isohumulone, on Adipocyte Function in Humans.

OBJECTIVE: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s). METHODS: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used to induce thermogenic gene expression. Adiponectin secretion was measured, and gene expression of 130 genes involved in adipose tissue function was determined. The effect of KDT501 on adipocyte mitochondrial function was analyzed in vitro. RESULTS: SC WAT explants secreted more total and HMW adiponectin after KDT501 treatment (P < 0.05). After KDT501 treatment, a number of genes involved in thermogenesis and lipolysis were induced by cold (P < 0.05). KDT501 also potentiated ß-adrenergic signaling (P < 0.001) and enhanced mitochondrial function in adipocytes (P < 0.001). CONCLUSION: KDT501 induced adiponectin secretion posttranscriptionally and increased gene expression of thermogenic and lipolytic genes in response to cold stimulation. These beneficial effects on SC WAT may be explained by the ability of KDT501 to potentiate ß-adrenergic signaling and enhance mitochondrial function in adipocytes. CLINICAL TRIAL REGISTRATION: https://www.ClinicalTrials.gov, ID number: NCT02444910.

[4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids as agonists of peroxisome proliferator-activated receptors (PPARs).

A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) alpha, gamma, and delta. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARalpha, and two of these, i.e., 1 and 5, exhibited also moderate activity on either PPARgamma or delta with efficacy equal to 50% and 46% of that of rosiglitazone and GW 501516, respectively. Thus, compounds 1 and 5 represent interesting starting point for preparing novel agents for the treatment of dyslipidemia or of dyslipidemic type-2 diabetes.

Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyperlipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPARalpha and PPARgamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARalpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPARalpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPARgamma agonist.

Bile acid signaling to the nucleus: finding new connections in the transcriptional regulation of metabolic pathways.

Recent findings indicate that the function of metabolically relevant genes is finely regulated at the level of gene transcription. Disturbances of these regulatory pathways often lead to metabolic unbalance and to the onset of socially relevant diseases, i.e. diabetes, metabolic syndrome, atherosclerosis and cardiovascular diseases. The ability of lipid metabolites, such as fatty acids and oxysterols, to signal to cells and tissues and to affect gene transcription by activating specific nuclear receptors has been known since several years. Bile acids have been known in the past as cholesterol end products, purely acting as detergents. Only recently new biological properties of bile acids as signaling molecules have been disclosed and appreciated. In this review, we will describe how bile acids can regulate their own synthesis and other metabolic pathways (i.e. glucose metabolism) by modulating gene transcription through multiple mechanisms. These findings also open new perspectives towards the exploitation of bile acid metabolism as a pharmacological target.

Consenso: seguridad del paciente y las metas internacionales / Patient safety and the international goals: Consensus document

La seguridad del paciente es una de las dimensiones de la atención. Los avances médicos han tornado los procesos de atención cada vez más complejos, y, usualmente, hay una conjunción de circunstancias que confluyen para que ocurran errores. Los eventos adversos constituyen un problema grave de salud pública al ocasionar daños de diversos grados al paciente y a su familia, lo cual, además, lleva a incrementar el costo del proceso de atención y la estancia hospitalaria.La mayoría de los eventos adversos se producen en los hospitales, ya que, por su complejidad, su población está sometida a un mayor riesgo asociado a la atención. Se presenta este consenso con el objetivo de ofrecer herramientas cuya implementación contribuya a brindar una atención más segura.

Patient safety is one of the dimensions of care. Medical advances have made assistance processes more and more complex, and there isusually a combination of circumstances that converge for errors to occur. Adverse events constitute a serious public health problem, causing damages of varying degrees to the patient and his family, which also leads to an increase in the cost of the care process and hospital stay. Most of the adverse events occur in hospitals because their complexity is subject to a greater risk associated with care. That is why we present this consensus with the aim of offering tools whose implementation can contribute to provide a safer healthcare.

Fluorescence resonance energy transfer techniques to study ligand-mediated interactions of PPARs with coregulators.

The capacity to induce the association of peroxisome proliferator-activated receptors (PPARs) with different transcriptional coregulators is determined by the peculiar 3D-structure that the receptors adopt when bound with a specific ligand. The fluorescence resonance energy transfer assay is a technique widely used to evaluate coregulator recruitment to nuclear receptors induced by ligands. With this assay it is possible to quantitatively determine the interaction and the affinity of coregulators with PPARs when these receptors are complexed with ligands. Here, we describe the use of this technique to assess the preferential interaction and the affinity of PPARγ with coregulators as a function of the chemical structure of the bound ligand.

Site-directed mutagenesis to study the role of specific amino acids in the ligand binding domain of PPARs.

The role of certain amino acids in the interactions of ligands with their cognate nuclear receptors is usually achieved by the resolution of the crystal structure of the receptor complexed with the ligand. As a complementary functional approach, site-directed mutagenesis, a technique broadly used in molecular biology, allows the assessment of the role of a specific amino acid in determining the interaction with a specific ligand. This method makes it possible to evaluate several mutations of a key amino acid for ligand binding and to determine the relationship between protein structure and ligand interaction. Here, we describe an application of this technique to evaluate different point mutations on the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ) in the absence or presence of chemically different ligands.

FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD region gene 1 (FRG1) since its over-expression in mice, Xenopus laevis and Caenorhabditis elegans, leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, we identify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to the muscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis.