Project description:As a co-transcriptional process, RNA processing, including alternative splicing and alternative polyadenylation, is crucial for the generation of multiple mRNA isoforms. RNA processing mechanisms are widespread across all higher eukaryotes and play critical roles in cell differentiation, organ development and disease response. Recently, significant progresses have been made in understanding the mechanism of RNA processing. RNA processing is regulated by trans-acting factors such as splicing factors, RNA-binding proteins and cis-sequences in pre-mRNA, and increasing evidence suggests that epigenetic mechanisms, which are important for the dynamic regulation and state of specific chromatic regions, are also involved in co-transcriptional RNA processing. In contrast, recent studies also suggest that alternative RNA processing also has a feedback regulation on epigenetic mechanisms. In this review, we discuss recent studies and summarize the current knowledge on the epigenetic regulation of alternative RNA processing. In addition, a feedback regulation of RNA processing on epigenetic regulators is also discussed.
Project description:BackgroundProstate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next-generation androgen receptor (AR) pathway inhibitors have acquired great success in treating PCa. However, patients treated with ADT or AR targeted therapy are inevitably developing into castration-resistant prostate cancer (CRPC) or becoming drug resistance. The role of mRNA 5-methylcytosine (m5C) modification in cancers is largely unknown. This study aimed to explore the role of the m5C methyltransferase NSUN2 in Prostate cancer (PCa).MethodsThe expression of NSUN2 and its clinicopathological impact were evaluated in PCa cohorts. The effect of NSUN2 on the biological characteristics of PCa cells was investigated on the basis of gain-offunction and loss-of-function analyses. Subcutaneous models further uncovered the role of NSUN2 in tumor growth. Epi-transcriptome assays with RNA bisulfite sequencing (RNA-BisSeq) analysis and in vitro enzyme reaction assays were performed to validate the targeted effect of NSUN2 on AR. AR-binding sites in the NSUN2 promoter were investigated by ChIP and luciferase assays to uncover the interplay between NSUN2 and AR signaling. RIP-qPCR and EMSA methods were performed to confirm that YBX1 binds to AR m5 C sites.ResultsNSUN2 is highly expressed in PCa and predicts poor outcome. NSUN2 plays roles as a PCa oncogene both in vitro and in vivo. Depletion of NSUN2 results in decreased expression and activities of AR, including AR-V7. Mechanistically, NSUN2 posttranscriptionally stabilized AR by cluster m5 C modification in a m5CYBX1-dependent manner. Strikingly, treatment with enzalutamide, an effective AR inhibitor, reduces NSUN2 expression and decreases the m5C modification level in prostate cancer cells. Finally, we found that AR transcriptionally regulates NSUN2.ConclusionNSUN2 stabilizes AR mRNA through cluster 5-methylcytosine modification and activates a positive feedback loop to promote prostate cancer.
Project description:BackgroundThe abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD+) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated.Scope of reviewThis review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use.Major conclusionsNNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer.
Project description:DNA methylation and nucleosome densities play a critical role in the regulation of gene expression. While much is known about the mechanisms of transcriptional control that are mediated by these, less is known about the degree to which they are tissue-specific. By comparing DNA methylation, nucleosome densities and transcriptional levels in different tissue types we can gain a clearer understanding of the extent to which these mechanisms influence gene expression in a tissue specific manner. We compared DNA methylation in Arabidopsis shoots and roots and found extensive differences across the genome. We computed DNA methylation differences between roots and shoots at single cytosines and found that one in every 173 cytosines was differentially methylated. In addition we compared DNA methylation with tissue specific gene expression and nucleosome density measurements to identify associations between these. We also identified a group of genes that are strongly correlated with these epigenetic marks and are significantly differentially methylated between roots and shoots. These root-specific genes are part of the extensin family, and are preferentially methylated and have at least 10-fold higher expression and lower nucleosome density in roots relative to shoots.
Project description:Asthma is a complex disease with genetic and environmental influences and emerging evidence suggests that epigenetic regulation is also a major contributor. Here, we focus on the developing paradigm that epigenetic dysregulation in asthma and allergy may start as early as in utero following several environmental exposures. We summarize the pathways important to the allergic immune response that are epigenetically regulated, the key environmental exposures associated with epigenetic changes in asthma genes, and newly identified epigenetic biomarkers that have been linked to clinical asthma. We conclude with a brief discussion about the potential to apply newly developing technologies in epigenetics to the diagnosis and treatment of asthma and allergy. The inherent plasticity of epigenetic regulation following environmental exposures offers opportunities for prevention using environmental remediation, measuring novel biomarkers for early identification of those at risk, and applying advances in pharmaco-epigenetics to tailor medical therapies that maximize efficacy of treatment. 'Precision Medicine' in asthma and allergy is arriving. As the field advances this may involve an individually tailored approach to the prevention, early detection, and treatment of disease based on the knowledge of an individual's epigenetic profile.
Project description:A still growing interest between human nutrition in relation to health and disease states can be observed. Dietary components shape the composition of microbiota colonizing our gastrointestinal tract which play a vital role in maintaining human health. There is a strong evidence that diet, gut microbiota and their metabolites significantly influence our epigenome, particularly through the modulation of microRNAs. These group of small non-coding RNAs maintain cellular homeostasis, however any changes leading to impaired expression of miRNAs contribute to the development of different pathologies, including neoplastic diseases. Imbalance of intestinal microbiota due to diet is primary associated with the development of colorectal cancer as well as other types of cancers. In the present work we summarize current knowledge with particular emphasis on diet-microbiota-miRNAs axis and its relation to the development of colorectal cancer.
Project description:Medulloblastoma is the most common malignant childhood brain tumor. The heterogeneous tumors are classified into four subgroups based on transcription profiles. Recent developments in genome-wide sequencing techniques have rapidly advanced the understanding of these tumors. The high percentages of somatic alterations of genes encoding chromatin regulators in all subgroups suggest that epigenetic deregulation is a major driver of medulloblastoma. In this report, we review the current understanding of epigenetic regulation in medulloblastoma with a focus on the functional studies of chromatin regulators in the initiation and progression of specific subgroups of medulloblastoma. We also discuss the potential usage of epigenetic inhibitors for medulloblastoma treatment.
Project description:Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.
Project description:Background: Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer propagation. It can be orchestrated by the activation of multiple signaling pathways, which have been found to be highly coordinated with many epigenetic regulators. Although the mechanism of EMT has been studied over decades, cross talk between signaling and epigenetic regulation is not fully understood.Results: Here, we present a time-resolved multi-omics strategy, which featured the identification of the correlation between protein changes (proteome), signaling pathways (phosphoproteome) and chromatin modulation (histone modifications) dynamics during TGF-β-induced EMT. Our data revealed that Erk signaling was activated in 5-min stimulation and structural proteins involved in cytoskeleton rearrangement were regulated after 1-day treatment, constituting a detailed map of systematic changes. The comprehensive profiling of histone post-translational modifications identified H3K27me3 as the most significantly up-regulated mark. We thus speculated and confirmed that a combined inhibition of Erk signaling and Ezh2 (H3K27me3 methyltransferase) was more effective in blocking EMT progress than individual inhibitions.Conclusions: In summary, our data provided a more detailed map of cross talk between signaling pathway and chromatin regulation comparing to previous EMT studies. Our findings point to a promising therapeutic strategy for EMT-related diseases by combining Erk inhibitor (singling pathway) and Ezh2 inhibitor (epigenetic regulation).
Project description:Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson's disease (PD) pathogenesis. Changes in gene expression are a well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the SNCA gene have demonstrated that gene dosage is associated with increased expression of both SNCA mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in SNCA expression caused by common variation is associated with disease risk. Of note, genome-wide association studies have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.