Epigenetic Regulatory Factors Research Articles

ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?

BackgroundProgrammed ribosomal frameshifting (PRF) is a gene expression mechanism which enables the translation of two N-terminally coincident, C-terminally distinct protein products from a single mRNA. Many viruses utilize PRF to control or regulate gene expression, but very few phylogenetically conserved examples are known in vertebrate genes. Additional sex combs-like (ASXL) genes 1 and 2 encode important epigenetic and transcriptional regulatory proteins that control the expression of homeotic genes during key developmental stages. Here we describe an ~150-codon overlapping ORF (termed TF) in ASXL1 and ASXL2 that, with few exceptions, is conserved throughout vertebrates.ResultsConservation of the TF ORF, strong suppression of synonymous site variation in the overlap region, and the completely conserved presence of an EH[N/S]Y motif (a known binding site for Host Cell Factor-1, HCF-1, an epigenetic regulatory factor), all indicate that TF is a protein-coding sequence. A highly conserved UCC_UUU_CGU sequence (identical to the known site of +1 ribosomal frameshifting for influenza virus PA-X expression) occurs at the 5′ end of the region of enhanced synonymous site conservation in ASXL1. Similarly, a highly conserved RG_GUC_UCU sequence (identical to a known site of −2 ribosomal frameshifting for arterivirus nsp2TF expression) occurs at the 5′ end of the region of enhanced synonymous site conservation in ASXL2.ConclusionsDue to a lack of appropriate splice forms, or initiation sites, the most plausible mechanism for translation of the ASXL1 and 2 TF regions is ribosomal frameshifting, resulting in a transframe fusion of the N-terminal half of ASXL1 or 2 to the TF product, termed ASXL-TF. Truncation or frameshift mutants of ASXL are linked to myeloid malignancies and genetic diseases, such as Bohring-Opitz syndrome, likely at least in part as a result of gain-of-function or dominant-negative effects. Our hypothesis now indicates that these disease-associated mutant forms represent overexpressed defective versions of ASXL-TF.ReviewersThis article was reviewed by Laurence Hurst and Eugene Koonin.

Polycomb silencing mediated by specific DNA-binding recruiters.

Regulation of epigenetic factors through their recruitment to specific genomic regions is still poorly understood. A recent study demonstrates a global mechanism of tethering Polycomb group (PcG) proteins through sequence-specific DNA-binding factors.

Mutations of ASXL1 gene in myelodysplastic syndromes

Objective To investigate the mutations of epigenetic regulation factor ASXL1 gene in myelodysplastic syndrome (MDS). Methods Mutation analysis of ASXL1 gene in 53 de novo MDS patients and 20 healthy persons was performed by using polymerase chain reaction (PCR) followed by sequence analysis at DNA level. The clinical and laboratory characteristics were compared in MDS patients with ASXL1 gene mutation and ASXL1 wild type. ASXL1 mutation in mRNA level was detected by using reverse transcription PCR (RT-PCR) followed by sequence analysis. Results ASXL1 gene mutations were observed in 9 cases(16.9 %) of 53 MDS patients.6 mutation types were detected, including 4 frameshift mutations types (2 cases with p.Glu635ArgfsX15, 3 cases with p.Gly646TrpfsX12, 1 case with p.Ala640GlyfsX14 and 1 case with p.Gly790TrpfsX10) and 2 nonsense mutation types (1 case with p.Gln1063X and 1 case with p.Gln695X). All the mutations were heterozygous, and p.Gly790TrpfsX10 and p.Gln695X were new mutation types. In addition, a single nucletide polymorphism (SNP) p.Gly652Ser was also detected in 4 cases with MDS. 5 cases of p.G652S SNP and 1 case of p.Leu1173Leu SNP were detected in 20 healthy people. Frameshift mutation (p.Gly646TrpfsX12) could be detected at mRNA level by using RT-PCR. Differences were not observed in red blood cell counts, white blood cell counts, platelet counts, hemoglobin levels, reticulocyte, neutrophil granulocyte, the peripheral blood lymphocytes percentage, T-cell subsets in the peripheral blood, the proportion of primitive cell in the marrow and MDS types between the patients with ASXL1 gene mutation and ASXL1 wild type patients (P > 0.05). Conclusion There is a high frequency of ASXL1 gene mutation in MDS patients, which can be detected at mRNA level. Key words: Gene, ASXL1; Myelodysplastic syndrome; Mutation; Epigenetic regulation factor

MicroRNA-125b is a key epigenetic regulatory factor that promotes nuclear transfer reprogramming

Somatic cell nuclear transfer (SCNT)-mediated reprogramming is a rapid, efficient, and sophisticated process that reprograms differentiated somatic cells to a pluripotent state. However, many factors in this elaborate reprogramming process remain largely unknown. Here, we report that the microRNA (miR) miR-125b is an important component of SCNT-mediated reprogramming. Luciferase reporter assay, quantitative PCR, and Western blotting demonstrated that miR-125b directly binds the 3′-untranslated region of SUV39H1, encoding the histone-lysine N-methyltransferase SUV39H1, to down-regulate histone H3 lysine-9 tri-methylation (H3K9me3) in SCNT embryos. Furthermore, the miR-125b/SUV39H1 interaction induced loss of SUV39H1-mediated H3K9me3, caused heterochromatin relaxation, and promoted the development of SCNT embryos. Transcriptome analyses of SCNT blastomeres indicated that HNF1 homeobox B (HNF1B), a gene encoding a transcription factor downstream of and controlled by the miR-125b/SUV39H1 axis, is important for conferring developmental competence on preimplantation embryos. We conclude that miR-125b promotes SCNT-mediated nuclear reprogramming by targeting SUV39H1 to decrease the deposition of repressive H3K9me3 modifications.

Artificial Intelligence, DNA Mimicry, and Human Health.

The molecular evolution of genomic DNA across diverse plant and animal phyla involved dynamic registrations of sequence modifications to maintain existential homeostasis to increasingly complex patterns of environmental stressors. As an essential corollary, driver effects of positive evolutionary pressure are hypothesized to effect concerted modifications of genomic DNA sequences to meet expanded platforms of regulatory controls for successful implementation of advanced physiological requirements. It is also clearly apparent that preservation of updated registries of advantageous modifications of genomic DNA sequences requires coordinate expansion of convergent cellular proofreading/error correction mechanisms that are encoded by reciprocally modified genomic DNA. Computational expansion of operationally defined DNA memory extends to coordinate modification of coding and previously under-emphasized noncoding regions that now appear to represent essential reservoirs of untapped genetic information amenable to evolutionary driven recruitment into the realm of biologically active domains. Additionally, expansion of DNA memory potential via chemical modification and activation of noncoding sequences is targeted to vertical augmentation and integration of an expanded cadre of transcriptional and epigenetic regulatory factors affecting linear coding of protein amino acid sequences within open reading frames.The burgeoning Artificial Intelligence (AI) discipline of biomolecular and DNA computing incorporates core operational machinery that includes input and output devices, memory, and biomolecular logic gates in order to utilize the potentially inexhaustible information technology (IT) capacity of genomic DNA [1]. Contextually, the dual application of DNA/RNA/protein complexed microcircuits to model AI deep learning and recurrent neural network paradigms carries the potential to significantly expand IT based strategies to effectively address a broad array of environmental challenges. Translational criteria to achieve effective augmentation of quality of life and life span require preemptive approaches to treat major disease states afflicting human populations from the perspective of personalized medicine that utilize reciprocally interactive genomic DNA databases [2,3]. To effectively advance these endeavors, the development of higher order AI-based bioinformatics based on complex cognitive processes linked to computational speed and accuracy may rely on evolutionary defined genomic DNA mimicry. The developmental elegance and critical biological importance of genomic DNA as a self-contained AI machine, crafted over the course of millions of years, establishes its primacy as the gold standard for design of higher order bioinformatics tools targeting human health processes. In summary, AI is not really artificial.

Epigenetic regulation of the pathological process in endometriosis.

BackgroundEndometriosis is one of the most common gynecological diseases that greatly compromises the quality of life in affected individuals. A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and microRNA expression.MethodsThis article retrospectively reviewed the studies that were related to the epigenetic regulatory factors that contribute to the development and maintenance of endometriosis. A literature search was performed in order to collect scientific articles that were written in English by using the key words of “endometriosis,” “epigenetics,” “DNA methylation,” “histone modification,” and “microRNA.”ResultsEpigenetic modifications, including DNA methylation, histone modification, and microRNA expression, are involved in the pathogenesis of endometriosis. These epigenetic players are regulated or tuned by microenvironmental cues, such as locally produced estradiol, proinflammatory cytokines, and hypoxic stress, and reciprocally regulate the process or response to those stimuli.ConclusionUnderstanding the molecular mechanisms that underlie these epigenetic regulatory processes would shed light on the etiology and/or progression of endometriosis and facilitate the development of novel therapeutic strategies.

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring.

It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). Genetic and metabolic alterations such as obesity, gestational diabetes mellitus (GDM), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (NDs) such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits. This review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in NDs. Furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.

Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy.

Wnt/β-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/β-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue. In this review, we summarize the conflicting published data regarding the Wnt/β-catenin signaling contribution to AC pathogenesis and we report the identification of a new potential therapeutic molecule that prevents myocyte injury and cardiac dysfunction due to desmosome mutations in vitro and in vivo by interfering in this signaling pathway. Finally, we underline the potential function of microRNAs, epigenetic regulatory RNA factors reported to participate in several pathological responses in heart tissue and in the Wnt signaling network, as important modulators of Wnt/β-catenin signaling transduction in AC.Elucidation of the precise regulatory mechanism of Wnt/β-catenin signaling in AC molecular pathogenesis could provide fundamental insights for new mechanism-based therapeutic strategy to delay the onset or progression of this cardiac disease.

The role of global histone post-translational modifications during mammalian hibernation

Mammalian hibernators must cope with hypothermia, ischemia-reperfusion, and finite fuel reserves during days or weeks of continuous torpor. One means of lowering ATP demands during hibernation involves substantial transcriptional controls. The present research analyzed epigenetic regulatory factors as a means of achieving transcriptional control over cycles of torpor-arousal. This study analyzes differential regulation of select histone modifications (e.g. phosphorylation, acetylation, methylation), and identifies post-translational modifications on purified histones using mass spectrometry from thirteen-lined ground squirrels (Ictidomys tridecemlineatus). Post-translational modifications on histone proteins were responsive to torpor-arousal, suggesting a potential mechanism to dynamically alter chromatin structure. Furthermore, proteomic sequencing data of ground squirrel histones identified lysine 19 and 24 acetylation on histone H3, while acetylation sites identified on H2B were lysine 6, 47, 110, and 117. The present study provides a new glimpse into the epigenetic mechanisms which may play a role in transcriptional regulation during mammalian hibernation.

The roles of Polycomb group proteins in hematopoietic stem cells and hematological malignancies.

Polycomb group (PcG) proteins are epigenetic regulatory factors that maintain the repression of target gene expression through histone modification. PcG proteins control the repression of genes that regulate differentiation and the cell cycle in the maintenance of hematopoietic stem cells (HSC). Moreover, abnormalities in expression level and mutations in PcG genes have been reported in various types of cancer, including hematological malignancies. In this review, we present an overview of the roles of PcG proteins in HSC and various types of hematological malignancies.

Effects of Novel ncRNA Molecules, p15-piRNAs, on the Methylation of DNA and Histone H3 of the CDKN2B Promoter Region in U937 Cells.

Non-coding RNAs (ncRNAs) play key roles in epigenetic events. However, the exact mechanism of ncRNA guidance, particularly piwi-interacting RNAs (piRNAs), for the targeting of epigenetic regulatory factors to specific gene regions is unclear. Although piRNA function was first established in germ-line cells, piRNA may be crucial in cancer cells. This study investigated the potential roles of CDKN2B-related piRNA in leukemia cells to provide a potential tumorigenesis model of leukemia. CDKN2B-related piRNAs, hsa_piR_014637 and hsa_piR_011186 were transduced into the leukemia cell line U937 to study the effect of these two piRNAs on cell-cycle progression, apoptosis, heterochromatin formation, CDKN2B methylation and expression. Our results show that over-expressing hsa_piR_011186 promoted cell-cycle progression and decreased apoptosis. We also observed inhibition of CDKN2B gene expression. These effects were likely mediated by novel piRC (piRNA complex) of CDKN2B-related piRNA that associate with DNMT1, Suv39H1 and/or EZH2 proteins to modulate the methylation of DNA and histone H3 in the promoter region of the CDKN2B gene. The novel piRC complex facilitated epigenetic modifications on the promoter of cell-cycle regulating genes, providing an expanded view of the role of piRNA in the progression of leukemia cells.

Molecular cloning, characterization and expression analysis of the protein arginine N-methyltransferase 1 gene (As-PRMT1) from Artemia sinica

Protein arginine N-methyltransferase 1 (PRMT1) is an important epigenetic regulation factor in eukaryotic genomes. PRMT1 is involved in histone arginine loci methylation modification, changes in eukaryotic genomes' chromatin structure, and gene expression regulation. In the present paper, the full-length 1201-bp cDNA sequence of the PRMT1 homolog of Artemia sinica (As-PRMT1) was cloned for the first time. The putative As-PRMT1 protein comprises 346 amino acids with a SAM domain and a PRMT5 domain. Multiple sequence alignments revealed that the putative sequence of As-PRMT1 protein was relatively conserved across species, especially in the SAM domain. As-PRMT1 is widely expressed during embryo development of A. sinica. This is followed by a dramatic upregulation after diapause termination and then downregulation from the nauplius stage. Furthermore, As-PRMT1 transcripts are highly upregulated under conditions of high salinity and low temperature stress. These findings suggested that As-PRMT1 is a stress-related factor that might promote or inhibit the expression of certain genes, play a critical role in embryonic development and in resistance to low temperature and high salinity stress.

A feedback regulation between miR-145 and DNA methyltransferase 3b in prostate cancer cell and their responses to irradiation

It is believed that epigenetic modification plays roles in cancer initiation and progression. Both microRNA and DNA methyltransferase are epigenetic regulation factors. It was found that miR-145 upregulates while DNMT3b downregulates in PC3 cells. Presence of any negative correlationship and their response to irradiation were investigated in the current study. We found that miR-145 downregulated DNMT3b expression by directly targeting the 3′-UTR of DNMT3b mRNA and knockdown of DNMT3b increased expression of miR-145 via CpG island promoter hypomethylation, suggesting that there is a crucial crosstalk between miR-145 and DNMT3b via a double-negative feedback loop. Responses of the miR-145 and DNMT3b to irradiation are a negative correlation. We also found that either overexpression of miR-145 or knockdown of DNMT3b sensitized prostate cancer cells to X-ray radiation. Our findings enrich the complex relationships between miRNA and DNMTs in carcinogenesis and irradiation stress. It also sheds light on the potential combination of ionizing radiation and epigenetic regulation in prostate cancer therapy.

Stem cell activation in skeletal muscle regeneration.

Muscle stem cell (satellite cell) activation post muscle injury is a transient and critical step in muscle regeneration. It is regulated by physiological cues, signaling molecules, and epigenetic regulatory factors. The mechanisms that coherently turn on the complex activation process shortly after trauma are just beginning to be illuminated. In this review, we will discuss the current knowledge of satellite cell activation regulation.

Abstract 2349: An RNA-based epigenetic network controls the expression of E-cadherin in epithelial normal and cancer cells

Abstract Epigenetic mechanisms play important roles in many human diseases. However, what drives epigenetic regulators to specific genomic locations is still an open question. Promoter-associated long non-coding RNAs (paRNAs) have been identified in many genes and have been proposed to act as docking elements for recruitment of epigenetic regulators to gene promoters, although the underlying mechanisms are still poorly characterized. In this study we investigated the role of paRNAs in transcriptional regulation of E-cadherin (CDH1), a trans-membrane glycoprotein and an important determinant of epithelial cell differentiation. Transcriptional silencing of E-cadherin is frequent in epithelial cancers and loss of E-cadherin expression triggers epithelial-to-mesenchymal transition (EMT) and acquisition of tumor-initiating properties. We found that bidirectional transcription occurred from independent initiation sites in the E-cadherin promoter and generated sense (S) and antisense (AS) paRNAs that coordinated the transcriptional activity of the gene. S and AS paRNAs had distinct expression patterns in normal and cancer cell lines and human prostate tumors. Both in cancer cell lines and human tumors the prevalence of S paRNAs and low AS/S paRNA ratio were associated with low E-cadherin expression. We found that the S paRNA bound Argonaute 1 (AGO1) and coordinated silencing of the gene by recruiting, along with AGO1, the histone methyltransferase SUV39H1 to the promoter. Consistently, knockdown of either S paRNA or AGO1 reduced SUV39H1 promoter occupancy and reactivated E-cadherin transcription in low expressing cells. Using promoter reporter and expression constructs we showed that the S paRNA and AGO1 acted in cis to control promoter activity and that the interaction with AGO1 required specific element of the S paRNA. Furthermore, recruitment of AGO1 to the S paRNA and CDH1 promoter depended on an isomiR derived through alternative processing and editing of pre-miR-4534. Accordingly, mutations that disrupted the isomiR binding sequence in the S paRNA reduced AGO1 binding and increased promoter activity, while depletion of the isomiR induced CDH1 expression. Notably, the novel isomiR was more abundant in transformed epithelial cells and cancer cell lines than normal prostate epithelial cells, accumulated preferentially in nuclei and was specifically associated with S paRNA and chromatin-bound AGO1 in low CDH1 expressing cancer cells. This study reveals a complex RNA-based epigenetic network that relies on sequence-specific interactions between a paRNA, a small RNA and AGO1 and coordinates transcriptional silencing of a critical gene involved in tumor development and progression. Our findings give also a new prospective and mechanistic insights on the interplay between epigenetic regulatory factors indentifying paRNAs as relevant elements in these processes and potential targets for gene modulation strategies. Citation Format: Sara Napoli, Giuseppina Pisignano, Ramon Garcia-Escudero, Giuseppina Carbone, Carlo V. Catapano. An RNA-based epigenetic network controls the expression of E-cadherin in epithelial normal and cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2349. doi:10.1158/1538-7445.AM2014-2349

RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer

PIWI-interacting small non-coding RNAs (piRNAs) are genetic and epigenetic regulatory factors in germline cells, where they maintain genome stability, are involved in RNA silencing and regulate gene expression. We found that the piRNA biogenesis and effector pathway are present in human breast cancer (BC) cells and, analyzing smallRNA-Seq data generated from BC cell lines and tumor biopsies, we identified >100 BC piRNAs, including some very abundant and/or differentially expressed in mammary epithelial compared to BC cells, where this was influenced by estrogen or estrogen receptor β, and in cancer respect to normal breast tissues. A search for mRNAs targeted by the BC piRNome revealed that eight piRNAs showing a specific expression pattern in breast tumors target key cancer cell pathways. Evidence of an active piRNA pathway in BC suggests that these small non-coding RNAs do exert transcriptional and post-transcriptional gene regulatory actions also in cancer cells.

Advances in the research on epigenetic regulation factors-SNF5 and EZH2 in the carcinogenesis and progress of different tumors

EpigeneticsreferstoheritablealterationsingeneexpressionthatdonotinvolvetheDNA coding sequence itself.Epigenetic regulation plays an important role in gene expression,DNA replication,rep-aration and reconstitution. Thus, the abnormity of epigenetic regulation may lead to different diseases, especially cancer.SNF5 ,which can suppress tumor significantly,is one of the core components of SWI/SNF chromosome remodeling complexes.EZH2,a histone methyltransferase,is closely and complicatedly related to cancer and has significant effect on tumorigenesis.There are many studies reporting the effects of epigenetic regulation factors-SNF5 and EZH2 on different tumors as well as the interrelation at present.In the present paper,the advances in the research on these two epigenetic regulation factors in the carcinogenesis are reviewed. Key words: Epigenesis,genetic; Neoplasms; Genesilencing

Ectopic expression of reprogramming factors enhances the development of cloned porcine embryos.

Inefficient cloning by somatic cell nuclear transfer (SCNT) is largely attributed to defects in epigenetic reprogramming. Reprogramming factors (RFs) (Oct4, Sox2, Klf4, c-Myc, Lin28 and Nanog; OSKMLN) can achieve epigenetic reprogramming, suggesting that these might facilitate reprogramming of oocytes. Here, porcine mesenchymal stem cells (pMSCs) treated with exogenous OSKMLN or OSKM were selected as nuclei donors for SCNT. The resulting embryos displayed significantly better development than controls in terms of cleavage rates and blastomere numbers. OSKM treatment improved pluripotency status and regulation of epigenetic factors in modified pMSCs. These changed gene patterns promoted H3K9Ac both in modified pMSCs and their SCNT-derived embryos. Thus, higher histone acetylation levels in donor cells might favor subsequent clone development. Application of exogenous RFs in SCNT offers a novel way for improving cloning efficiency.

Unhealthy Nutrigenomic Diets Accelerate NAFLD and Adiposity in Global communities

The understanding of genetic factors involved in the risk for obesity has identified genes that are closely linked to obesity related diseases. A single gene effect versus multiple genes effect may indicate either the interaction unique to various environments that regulate abnormal molecular or cellular events responsible for obesity with several hypotheses proposed in relation to the development of obesity. The understanding of the development of adipogenesis has been the focus of the global community with obesity genetics, epigenetic regulatory mechanisms and transcription factors important to the world-wide obesity epidemic with increased risk for adiposity. The search for specific genes that are sensitive to nutritional regulation, oxidative stress, inflammation, endocrine disease, lipid/ glucose metabolism, insulin resistance and Alzheimer’s disease has been the focus of the current obesity epidemic in various developed countries. Epigenetics is now considered as an important mechanism for the development of obesity and can result from changes in cellular chromatin structure without alterations in DNA sequence, including DNA methylation, histone modifications and chromatin remodelling. Epigenetic modifications induced by unhealthy diets and the environment effect nuclear/mitochondria interactions and implicate nuclear receptors such as Sirt 1 as a single gene effect with interactions with microRNA and transcription factors such as p53 that regulate cellular and immune events with effects on cellular lipid metabolism and energy expenditure that induce senescence with poor DNA repair. Epigenetic modifications in various communities are now closely involved in NAFLD associated with excess transfer of fat to the adipose tissue and the induction of obesity in developed countries. The failure of various anti-obese drugs has encouraged the use of nutrigenomic diets that reverse senescence and assist in the early nutritional intervention that reverses NAFLD with reduced adiposity.

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications.