Epigenetic Modulation Of Gene Expression Research Articles

Epigenetic potential affects immune gene expression in house sparrows.

Epigenetic mechanisms may play a central role in mediating phenotypic plasticity, especially during range expansions, when populations face a suite of novel environmental conditions. Individuals may differ in their epigenetic potential (EP; their capacity for epigenetic modifications of gene expression), which may affect their ability to colonize new areas. One form of EP, the number of CpG sites, is higher in introduced house sparrows (Passer domesticus) than in native birds in the promoter region of a microbial surveillance gene, Toll-like Receptor 4 (TLR4), which may allow invading birds to fine-tune their immune responses to unfamiliar parasites. Here, we compared TLR4 gene expression from whole blood, liver and spleen in house sparrows with different EP, first challenging some birds with lipopolysaccharide (LPS), to increase gene expression by simulating a natural infection. We expected that high EP would predict high inducibility and reversibility of TLR4 expression in the blood of birds treated with LPS, but we did not make directional predictions regarding organs, as we could not repeatedly sample these tissues. We found that EP was predictive of TLR4 expression in all tissues. Birds with high EP expressed more TLR4 in the blood than individuals with low EP, regardless of treatment with LPS. Only females with high EP exhibited reversibility in gene expression. Further, the effect of EP varied between sexes and among tissues. Together, these data support EP as one regulator of TLR4 expression.

Current Status of Functional Studies on Circular RNAs in Rheumatoid Arthritis and Their Potential Role as Diagnostic Biomarkers.

Circular RNAs (circRNAs), a new class of endogenous non-coding RNAs (ncRNAs), are highly stable and exhibit tissue-specific expression. Accumulating evidence has indicated that circRNAs play crucial roles in the development and progression of multiple diseases. Notably, circRNAs, important epigenetic modulators of gene expression in inflammation and autoimmune regulation, have a close association with the pathogenesis of rheumatoid arthritis (RA). RA, one of the most common systemic autoimmune diseases, is characterized by synovial hyperplasia and inflammation, and cartilage and bone destruction. Here, we focus on the roles of circRNAs in macrophage, synovial tissues, fibroblast-like synoviocytes (FLSs), and cartilage tissues in pathogenesis and progression of RA, highlighting the potential of circRNAs in the blood as diagnostic biomarkers, and aiming at providing new insights into the diagnosis and therapy of this disease.

PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance.

Epigenetic modulation of gene expression is essential for tissue-specific development and maintenance in mammalian cells. Disruption of epigenetic processes, and the subsequent alteration of gene functions, can result in inappropriate activation or inhibition of various cellular signaling pathways, leading to cancer. Recent advancements in the understanding of the role of epigenetics in cancer initiation and progression have uncovered functions for DNA methylation, histone modifications, nucleosome positioning, and non-coding RNAs. Epigenetic therapies have shown some promise for hematological malignancies, and a wide range of epigenetic-based drugs are undergoing clinical trials. However, in a dynamic survival strategy, cancer cells exploit their heterogeneous population which frequently results in the rapid acquisition of therapy resistance. Here, we describe novel approaches in drug discovery targeting the epigenome, highlighting recent advances the selective degradation of target proteins using Proteolysis Targeting Chimera (PROTAC) to address drug resistance.

Design, synthesis, computational and biological evaluation of novel hydroxamic and carboxylic acid derivatives as histone decaetylase inhibitors

One of the recent targets is histone deacetylase (HDAC) which provide a very promising new approach for anticancer drugs, which may combine clinical efficacy with relatively mild toxicological side effects. Modification of histone acetylation level, promoted by histone acetylase (HAT) and HDAC enzyme, has been recognize to play an important role in epigenetic modulation of gene expression, so HDAC inhibitors are considered a new class of anticancer agents. A new series of hydroxamic and carboxylic acid analogues based on the 1,3,4-thiadiazole scaffold has been designed and synthesized with the aim of exploring its potential as new antitumor agents. Biological results have revealed that the structural modifications proposed significantly affected inhibitory potency as well as selectivity for HDAC inhibitors. Most target compounds are significantly more active, specifically 5a , 5b , 5e with IC 50 values in the low micromolar or, the most active compounds in the series. Selected compounds have been tested on the viability of MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell), A549 (human lung cancer), PC3 (Prostate cancer cell lines) using MTT assay. Docking simulations suggested that the most active compounds can recognize the binding site (PDB Code 1w22 reference compound) using a similar interactions network. These results have allowed us to rationalize the observed structure–activity relationships.

Research progress on the expression and carcinogenic mechanisms of SETD2 in malignant tumors

The human epigenetic gene of SET domain containing 2 (SETD2) is located at the cytogenetic band p21.31 of chromosome 3, which encodes the histone3 lysine36 trimethyltransferase SETD2, the major enzyme that catalyzes the trimethylation of lysine 36 on histone 3 (H3K36me3) of human. SETD2 involves in many pathologic and physiological processes such as transcriptional elongation, DNA damage repair, alternative splicing, epigenetic modifications of gene expression, viral immunology, embryonic development, and angiogenesis. A growing list of tumor types including renal cell carcinoma and mesothelioma develops with mutation or inactivation of SETD2. SETD2 loss-of-function promotes the occurrences and development of cancers by inhibiting process of transcription extension, damage repair, cell cycles, apoptosis and cell metabolism. The under expression and mutation of SETD2 is synthetically lethal with the inhibition of G2M checkpoint and PI3K-AKT pathway and SETD2 is considered as a potential epigenetic therapy targets. Furthermore, a loss of SETD2 indicates worse pathological features. There are huge prospects in the diagnosis and treatment of related cancers.

Stability of Smyd1 in endothelial cells is controlled by PML-dependent SUMOylation upon cytokine stimulation.

Smyd1 is an epigenetic modulator of gene expression that has been well-characterized in muscle cells. It was recently reported that Smyd1 levels are modulated by inflammatory processes. Since inflammation affects the vascular endothelium, this study aimed to characterize Smyd1 expression in endothelial cells. We detected Smyd1 in human endothelial cells (HUVEC and EA.hy926 cells), where the protein was largely localized in PML nuclear bodies (PML-NBs). By transfection of EA.hy926 cells with expression vectors encoding Smyd1, PML, SUMO1, active or mutant forms of the SUMO protease SuPr1 and/or the SUMO-conjugation enzyme UBC9, as well as Smyd1- or PML-specific siRNAs, in the presence or absence of the translation blocker cycloheximide or the proteasome-inhibitor MG132, and supported by computational modeling, we show that Smyd1 is SUMOylated in a PML-dependent manner and thereby addressed for degradation in proteasomes. Furthermore, transfection with Smyd1-encoding vectors led to PML up-regulation at the mRNA level, while PML transfection lowered Smyd1 protein stability. Incubation of EA.hy926 cells with the pro-inflammatory cytokine TNF-α resulted in a constant increase in Smyd1 mRNA and protein over 24 h, while incubation with IFN-γ induced a transient increase in Smyd1 expression, which peaked at 6 h and decreased to control values within 24 h. The IFN-γ-induced increase in Smyd1 was accompanied by more Smyd1 SUMOylation and more/larger PML-NBs. In conclusion, our data indicate that in endothelial cells, Smyd1 levels are regulated through a negative feedback mechanism based on SUMOylation and PML availability. This molecular control loop is stimulated by various cytokines.

Emerging roles of long noncoding RNAs in cholangiocarcinoma: Advances and challenges.

Cholangiocarcinoma (CCA), a cancer with a relatively low incidence rate, is usually associated with poor prognosis. Current modalities for the diagnosis and treatment of CCA patients are still far from satisfactory. In recent years, numerous long noncoding RNAs (lncRNAs) have been identified as crucial players in the development of various cancers, including CCA. Abnormally expressed lncRNAs in CCA, regulated by some upstream molecules, significantly influence the biological behavior of tumor cells and are involved in tumor development through various mechanisms, including interactions with functional proteins, participation in competing for endogenous RNA (ceRNA) regulatory networks, activation of cancer‐related signaling pathways and epigenetic modification of gene expression. Furthermore, several lncRNAs are closely associated with the clinicopathological features of CCA patients, and are promising biomarkers for diagnosing and prognostication of CCA. Some of these lncRNAs play an important role in chemotherapy drug resistance. In addition, lncRNAs have also been shown to be involved in the inflammation microenvironment of CCA and malignant outcome of CCA risk factors, such as cholestatic liver diseases. In view of the difficulty of diagnosing CCA, more attention should be paid to detectable lncRNAs in the serum or bile. This review summarizes the recent knowledge on lncRNAs in CCA and provides a new outlook on the molecular mechanisms of CCA development from the perspective of lncRNAs. Moreover, we also discussed the limitations of the current studies and differential expression of lncRNAs in different types of CCA.

Protective action of the microbial metabolite butyrate against cardiomyocyte hypertrophy

Abstract Introduction Short-chain fatty acids are one of the gut microbial metabolites that may influence host physiology. We previously reported that gut dysbiosis was associated with heart failure, and that the proportions of butyrate-producing bacteria diminished prominently in the gut of patients with heart failure. Purpose We investigated the molecular mechanism of butyrate and investigated the protective mechanism against heart failure. Methods We searched for G protein-coupled receptors for short-chain fatty acids using single-cell transcriptome analysis of cardiomyocytes and non-cardiomyocytes isolated from murine hearts. In addition, we examined the effects of butyrate on endothelin-1 (ET1) or isoproterenol-induced hypertrophic responses and histone deacetylase (HDAC) activities in cultured neonatal rat cardiomyocytes. Results Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. Treatment with butyrate inhibited ET1-induced hypertrophic growth and up-regulation of the genes such as Nppa, Acta1, and Myh7 in cultured rat neonatal cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, indicating that butyrate has an inhibitory effect on HDAC in cardiomyocytes. In addition, treatment with butyrate caused up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, which was associated with a significant decrease in the phosphorylation levels of Akt. These results suggest that butyrate may act as HDAC inhibitor to increase Inpp5f gene expression, leading to the activation of Akt-glycogen synthase kinase 3beta (Gsk3beta) pathway, and thereby protect against hypertrophic responses. Conclusion There was no known GPCR for short-chain fatty acid expressed in cardiomyocytes. However, butyrate suppressed cardiomyocyte hypertrophy through epigenetic modification of gene expression. Our results may uncover a potential role of the dysbiosis of intestinal microbiota in the pathogenesis of cardiac hypertrophy and failure. Funding Acknowledgement Type of funding source: None

Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic

Sex as a biological variable plays a critical role both during lung development and in modulating postnatal hyperoxic lung injury and repair. The molecular mechanisms behind these sex-specific differences need to be elucidated. Our objective was to determine if the neonatal lung epigenomic landscape reconfiguration has profound effects on gene expression and could underlie sex-biased differences in protection from or susceptibility to diseases. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (95% FiO, PND 1–5: saccular stage) or room air and euthanized on PND 7 and 21. Pulmonary gene expression was studied using RNA-seq on Illumina HiSeq 2500 platform and quantified. Epigenomic landscape was assessed using Chromatin Immunoprecipitation (ChIP-Seq) of the H3K27ac histone modification mark, associated with active genes, enhancers, and super-enhancers. These data were then integrated, pathways identified and validated. Sex-biased epigenetic modulation of gene expression leads to differential regulation of biological processes in the developing lung at baseline and after exposure to hyperoxia. The female lung exhibits a more robust epigenomic response for the H3K27ac mark in response to hyperoxia. Epigenomic changes distribute over genomic and epigenomic domains in a sex-specific manner. The differential epigenomic responses also enrich for key transcription regulators crucial for lung development. In addition, by utilizing H3K27ac as the target epigenomic change we were also able to identify new epigenomic reprogramming at super-enhancers. Finally, we report for the first time that the upregulation of p21 (Cdkn1a) in the injured neonatal lung could be mediated through gain of H3K27ac. These data demonstrate that modulation of transcription via epigenomic landscape alterations may contribute to the sex-specific differences in preterm neonatal hyperoxic lung injury and repair.

QSAR Modeling, Molecular Docking and Molecular Dynamics Simulations Studies of Lysine-Specific Demethylase 1 (LSD1) Inhibitors as Anticancer Agents

Histone Lysine Demetylases1 (LSD1) is a promising medication to treat cancer, which plays a crucial role in epigenetic modulation of gene expression. Inhibition of LSD1with small molecules has emerged as a vital mechanism to treat cancer. In the present research, molecular modeling investigations, such as CoMFA, CoMFA-RF, CoMSIA and HQSAR, molecular docking and Molecular Dynamics (MD) simulations were carried out on some tranylcypromine derivatives as LSD1 inhibitors. The QSAR models were carried out on a series of Tranylcypromine derivatives as data set via the SYBYL-X2.1.1 program. Molecular docking and MD simulations were carried out by the MOE software and the SYBYL program, respectively. The internal and external predictability performances related to the generated models for these LSD1 inhibitors were justified by evaluating cross-validated correlation coefficient (q2), noncross- validated correlation coefficient (r2ncv) and predicted correlation coefficient (r2pred) of the training and test set molecules, respectively. The CoMFA (q2, 0.670; r2ncv, 0.930; r2pred, 0.968), CoMFA-RF (q2, 0.694; r2ncr, 0.926; r2pred, 0.927), CoMSIA (q2, 0.834; r2ncv, 0.956; r2pred, 0.958) and HQSAR models (q2, 0.854; r2ncv, 0.900; r2pred, 0.728) for training as well as the test set of LSD1 inhibition resulted in significant findings. These QSAR models were found to be perfect and strong with better predictability. Contour maps of all models were generated and it was proven by molecular docking studies and molecular dynamics simulation that the hydrophobic, electrostatic and hydrogen bonding fields are crucial in these models for improving the binding affinity and determining the structure-activity relationship. These theoretical results are possibly beneficial to design new strong LSD1 inhibitors with enhanced activity to treat cancer.

Dissecting the functional pleiotropism of lysine demethylase 5B in physiology and pathology

Background: The last two decades has been characterized by accruing evidence of the translational relevance of chromatin modification in normal genomic function, regulation, and pathology, especially with piqued interest in the intrinsic regulatory dynamism of histone methylation, and the increasing documentation of new members of the histone demethylase family. Recent studies provide functional and mechanistic insight into the peculiar biological role of these histone demethylases and their putative implication in pathological processes. Objective: This review aims to provide a summary of the latest findings related to pleiotropic roles of the Jumonji/AT-rich interactive domain (JARID) domain-containing lysine demethylase 5B (KDM5B, also known as JARID1B or PLU1) in physiology and pathology, with a focus on its therapeutic potentials. Results: KDM5B/JARID1B/PLU1 is restrictively expressed, evolutionarily conserved across mammalian species, and belonging to the α-ketoglutarate-dependent hydroxylase superfamily. KDM5B is actively involved in various physiological processes, including regulation of transcription elongation and alternative splicing in embryonic stem cells, epigenetic modulation of gene expression, neurogenesis, mammary gland development, and osteogenesis. Conversely, KDM5B is one of the earliest identified histone lysine demethylases associated with human disease, with several studies indicating that KDM5B plays a vital role in the initiation and progression of various malignancies, including lung, hypopharynx, brain, and breast cancers. Conclusion: This study provides concise insight into the functional pleiotropism of KDM5B in physiology and pathology, as well as highlights it role as an actionable therapeutic target.

Environmental change and the evolution of genomes: Transposable elements as translators of phenotypic plasticity into genotypic variability

Abstract Phenotypic plasticity is generally explained as the result of epigenetic mechanisms modifying gene expression in response to changing environmental conditions. However, the biology of transposable elements (TEs) suggests that such elements may also induce differential gene expression by affecting regulatory regions. We discuss the ecological and evolutionary relevance of epigenetic modifications versus transposon activity, taking into account that epigenetic modifications are generally reversible but that the modifications induced by TEs are stably inherited. We outline our perspective on the multiple roles played by environmental changes in the context of adaptive evolution. Environmental perturbations can induce phenotypic variations via epigenetic modulation of gene expression and promote, at the same time, genetic variability by triggering bursts of TE activity; finally, they select which genetic variations are most advantageous for survival. Within this context, the production of environmentally induced advantageous phenotypes by epigenetic mechanisms could represent an immediate process of adaptation followed by TE‐induced genotypic changes that make these phenotypic variants heritable through the germ line. This scenario could lead TEs to play different roles in the function of the time‐scale of ecological variation, such as those related to climatic change in the current context of global change. In conclusion, we propose that through TE activation, environmental changes can act as inducers of genetic variability, upon which they also act as selective forces, thus triggering rapid evolutionary processes. A free Plain Language Summary can be found within the Supporting Information of this article.

The adaptive value of epigenetic mutation: Limited in large but high in small peripheral populations.

The fate of populations during range expansions, invasions and environmental changes is largely influenced by their ability to adapt to peripheral habitats. Recent models demonstrate that stable epigenetic modifications of gene expression that occur more frequently than genetic mutations can both help and hinder adaptation in panmictic populations. However, these models do not consider interactions between epimutations and evolutionary forces in peripheral populations. Here, we use mainland-island mathematical models and simulations to explore how the faster rate of epigenetic mutation compared to genetic mutations interacts with migration, selection and genetic drift to affect adaptation in peripheral populations. Our model focuses on cases where epigenetic marks are stably inherited. In a large peripheral population, where the effect of genetic drift is negligible, our analyses suggest that epimutations with random fitness impacts that occur at rates as high as 10-3 increase local adaptation when migration is strong enough to overwhelm divergent selection. When migration is weak relative to selection and epimutations with random fitness impacts decrease adaptation, we find epigenetic modifications must be highly adaptively biased to enhance adaptation. Finally, in small peripheral populations, where genetic drift is strong, epimutations contribute to adaptation under a wider range of evolutionary conditions. Overall, our results suggest that epimutations can change outcomes of adaptation in peripheral populations, which has implications for understanding conservation and range expansions and contractions, especially of small populations.

Circulating miRNAs as Diagnostic and Prognostic Biomarkers in Common Solid Tumors: Focus on Lung, Breast, Prostate Cancers, and Osteosarcoma.

An early cancer diagnosis is essential to treat and manage patients, but it is difficult to achieve this goal due to the still too low specificity and sensitivity of classical methods (imaging, actual biomarkers), together with the high invasiveness of tissue biopsies. The discovery of novel, reliable, and easily collectable cancer markers is a topic of interest, with human biofluids, especially blood, as important sources of minimal invasive biomarkers such as circulating microRNAs (miRNAs), the most promising. MiRNAs are small non-coding RNAs and known epigenetic modulators of gene expression, with specific roles in cancer development/progression, which are next to be implemented in the clinical routine as biomarkers for early diagnosis and the efficient monitoring of tumor progression and treatment response. Unfortunately, several issues regarding their validation process are still to be resolved. In this review, updated findings specifically focused on the clinical relevance of circulating miRNAs as prognostic and diagnostic biomarkers for the most prevalent cancer types (breast, lung, and prostate cancers in adults, and osteosarcoma in children) are described. In addition, deep analysis of pre-analytical, analytical, and post-analytical issues still affecting the circulation of miRNAs’ validation process and routine implementation is included.

Abstract 2481: Developing analysis platform for pan-cancer study of DNA methylation, mirna and lncrna expression based on tumor subtypes using TCGA data

Abstract Introduction: The Cancer Genome Atlas (TCGA) consortium performed high-throughput sequencing of thousands of tumor and normal tissues across 33 cancer types. This has led to molecular characterization of different cancers and many novel discoveries. Such diverse data offers an excellent opportunity to further address the questions associated with tumor heterogeneity. Systematic exploration of epigenetic features and non-coding gene expression could lead clinicians/cancer researchers towards unearthing new diagnostic biomarkers and therapeutic targets. Previously our group developed a cancer transcriptome web portal, UALCAN [http://ualcan.path.uab.edu, Google: UALCAN)] to study expression and survival profile of protein coding genes among TCGA cancers based on various subgroups and molecular subtypes of cancer. Although many data portals facilitating easy access and in-depth analysis of TCGA data exists, there is need for a user-friendly resource facilitating comprehensive DNA methylation profile and gene expression analysis of lncRNA and miRNA within tumor subgroups based on factors such as stage, tumor grade, age, sex, race and integration with the gene expression. Methods: TCGA Level 3 RNA-seq, miRNA-seq and Illumina Infinium HumanMethylation450K data were downloaded using TCGA-Assembler 2 tool and Genomic Data Commons (GDC). The data were processed, organized based on tumor subtypes using custom R scripts. DNA methylation and gene expression analysis was performed using in-house PERL scripts, while statistical significance was estimated using “Statistics::TTest” module. The analyses results were stored as flat file database and hosted on a web portal developed using Apache2.0, PERL-CGI and HighChartJS JavaScript libraries. Results: The user friendly web portal 1) allows users could obtain list of top over-/under-expressed miRNAs and lncRNAs in each of 33 TCGA cancer 2) facilitates analysis of promoter methylation level and gene expression for given set of miRNA/ lncRNAs in various tumor sub-groups based on individual cancer stages, tumor grade, race, body weight or other clinicopathologic features, 3) enables researchers to download high resolution graphics such as heatmap, boxplots, dotplots as analyses outputs. The data can be downloaded in multiple output formats for use by researchers. Conclusion: The current resource aids cancer researchers in identifying DNA methylation mediated epigenetic modification of gene expression in tumor subgroup specific manner. Furthermore, our platform will facilitate analyses of long non-coding RNAs and microRNAs, thereby help in discovery of novel biomarkers and better understanding of the tumor biology. Citation Format: Darshan Shimoga Chandrashekar, Chad J. Creighton, Israel Ponce-Rodriguez, Sooryanarayana Varambally. Developing analysis platform for pan-cancer study of DNA methylation, mirna and lncrna expression based on tumor subtypes using TCGA data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2481.

Eruca sativa L-A promising source of drug lead for antimicrobial, neuroprotective and anticancer treatment regimens: Pharmacological properties of medicinal plant “Eruca sativa”

Rocket (Eruca sativa) is a low-calorie leafy vegetable of the family Brassicaceae under the genera Eruca mostly consumed raw in salads. It has been used since ancient times from food to medicine and cosmetics without any knowledge of the mechanism or the targets involved. However, presently, the production and cultivation of rocket have significantly increased owing to its different biological effects. Erucin and Sulforaphane are the most commonly studied isothiocyanates obtained from the plant parts of Eruca sativa. Over time, with continuous usage of conventional and synthetic drugs, the drug resistant and off-target toxicities rapidly increase, which necessitates for alternative medicine with increased specificity and minimal detrimental effects. It is interesting to note that many previous studies have reported the antimicrobial impact of E. sativa against the pathogenic bacterial species like Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, etc. Moreover, Erucin obtained from E. sativa has shown significant inhibitory and protective effect against different human cancer cell lines and xenograft animal models. The present review gives a brief overview of the antimicrobial, neuroprotective and anticancer effects of the various plant parts of E. sativa and the most bioactive isothiocyanates. It is exciting to note that epigenetic modulation of gene expression has also been reported in some studies which could be a new direction of research on the path of naturopathy.

An Overview of the Epigenetic Modifications of Gene Expression in Tumorigenesis

The five leading causes of cancer-related deaths are lung (1,760,000 deaths), colorectal (862,000 deaths), stomach (783,000 deaths), liver (782,000 deaths), and breast (627,000 deaths) cancers. Epigenetic changes can alter chromatin compaction, leading to the regulation of gene expression without changing the primary DNA sequence. Epigenetic mechanisms are normally involved in cellular processes such as genomic stability, chromosome X inactivation, and embryonic development and differentiation. Similar to other types of chromatin modifications, DNA methylation has been verified to affect the expression of various genes. Any impairment in these mechanisms alters the regulation of gene expression and can contribute to malignant cell transformation. Over the past few years, extensive innovations within the field of epigenetics have encouraged its application as a major strategy for the treatment of important diseases such as cancer.

Circulating miRNAs as Biomarkers for Endometriosis and Endometriosis-Related Ovarian Cancer-An Overview.

Early detection and accurate diagnosis are pivotal in the management of endometriosis and endometriosis-related ovarian neoplasms (ERONs), yet there is no clear common ground regarding their pathogenesis. Endometriosis is a debilitating pathology that profoundly impairs the quality of life. Although the spontaneous resolution of endometriosis is possible, studies suggest that it can be a progressive condition, and ERONs can develop. The gold standard for diagnosis remains as the invasive method of laparoscopy followed by histological confirmation. In recent years, novel biomarkers have been discovered. MicroRNAs (miRNA) represent important epigenetic modulators of gene expression and are very attractive as biomarkers due to their lower complexity, tissue specificity, and stability in bodily fluids. Several studies have advanced the possibility of miRNAs becoming potential biomarkers in endometriosis and ERONs. Our aim is to bring these studies together in order to have a better understanding of whether, how, and when miRNAs might be used as biomarkers for these pathologies. Methods: We selected the reviewed papers from Google Academic, PubMed, and CrossRef. A total of eight studies met the inclusion criteria. Results: MiR-200 family, miR-143, 145, miR-20a, and miR199a were the most commonly dysregulated miRNAs in endometriosis, and miR-200 family was found to be dysregulated in both ERONs and endometriosis. Conclusions: No single miRNA was considered as a sole biomarker for this pathology. However, since the prognostic value of biomarkers is generally enhanced if more are assessed at the same time, a panel of miRNAs could be a better indicator of the disease.

Targeted inhibition of histone deacetylase 6 in inflammatory diseases

Targeting epigenetic modification of gene expression represents a promising new approach under investigation for the treatment of inflammatory diseases. Accumulating evidence suggests that epigenetic mechanisms, such as histone modification, play a crucial role in a number of inflammatory diseases, including rheumatoid arthritis, asthma, and contact hypersensitivity. Consistent with this role, histone deacetylase (HDAC) inhibitors have shown efficacy in the treatment of inflammatory diseases. In particular, selective inhibitors of HDAC6, a cytoplasmic member of the HDAC family that contains two deacetylase domains, are under investigation as a potential treatment strategy for inflammatory diseases due to their ability to regulate inflammatory cells and cytokines. Here, we review recent findings highlighting the critical roles of HDAC6 in a variety of inflammatory diseases, and discuss the therapeutic potential of HDAC6 inhibitors in these settings.

Selective Small-Molecule Targeting of a Triple Helix Encoded by the Long Noncoding RNA, MALAT1.

Metastasis-associated lung adenocarcinoma transcript 1 ( Malat1/ MALAT1, mouse/human), a highly conserved long noncoding (lnc) RNA, has been linked with several physiological processes, including the alternative splicing, nuclear organization, and epigenetic modulation of gene expression. MALAT1 has also been implicated in metastasis and tumor proliferation in multiple cancer types. The 3' terminal stability element for nuclear expression (ENE) assumes a triple-helical configuration that promotes its nuclear accumulation and persistent function. Utilizing a novel small molecule microarray strategy, we identified multiple Malat1 ENE triplex-binding chemotypes, among which compounds 5 and 16 reduced Malat1 RNA levels and branching morphogenesis in a mammary tumor organoid model. Computational modeling and Förster resonance energy transfer experiments demonstrate distinct binding modes for each chemotype, conferring opposing structural changes to the triplex. Compound 5 modulates Malat1 downstream genes without affecting Neat1, a nuclear lncRNA encoded in the same chromosomal region as Malat1 with a structurally similar ENE triplex. Supporting this observation, the specificity of compound 5 for Malat1 over Neat1 and a virus-coded ENE was demonstrated by nuclear magnetic resonance spectroscopy. Small molecules specifically targeting the MALAT1 ENE triplex lay the foundation for new classes of anticancer therapeutics and molecular probes for the treatment and investigation of MALAT1-driven cancers.