Role Of Epigenetic Modulation Research Articles

Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions.

Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.

DNA Methylation Signature of Synchronous Endometrioid Endometrial and Ovarian Carcinomas

Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC.

SARS-CoV-2 variants, its recombinants and epigenomic exploitation of host defenses

Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to unique viral traits, allowing its rapid global dissemination following its emergence in October 2019 in Wuhan, China, which appears to be primarily driven by the emergence of highly transmissible and virulent variants that also associate, in some cases, with severe disease and considerable mortality caused by fatal pneumonia, acute respiratory distress syndrome (ARDS) in infected individuals.Mechanistically, several factors are involved in viral pathogenesis, and epigenetic alterations take the front seat in host-virus interactions. The molecular basis of all viral infections, including SARS-CoV-2, tightly hinges on the transitory silencing of the host gene machinery via epigenetic modulation. SARS-CoV-2 also hijacks and subdues the host gene machinery, leading to epigenetic modulation of the critical host elements responsible for antiviral immunity. Epigenomics is a powerful, unexplored avenue that can provide a profound understanding of virus-host interactions and lead to the development of epigenome-based therapies and vaccines to counter viruses. This review discusses current developments in SARS-CoV-2 variation and its role in epigenetic modulation in infected hosts. This review provides an overview, especially in the context of emerging viral strains, their recombinants, and their possible roles in the epigenetic exploitation of host defense and viral pathogenesis. It provides insights into host-virus interactions at the molecular, genomic, and immunological levels and sheds light on the future of epigenomics-based therapies for SARS-CoV-2 infection.

The new advance of SALL4 in cancer: Function, regulation, and implication.

SALL4 (split-like protein 4) is a member of the mammalian homologs of the Drosophila homoeotic gene spalt (sal) and acts as a zinc finger transcription factor to govern the self-renewal and pluripotency of embryonic stem cells. SALL4 expression gradually decreases during development and is even absent in most adult tissues. However, increasing evidence suggests that SALL4 expression is restored in human cancers and its aberrant expression is associated with the progression of many hematopoietic malignancies and solid tumors. The potent roles of SALL4 in regulating cancer cell proliferation, apoptosis, metastasis, and drug resistance have been reported. SALL4 plays a dual role in epigenetic modulation by acting as either an activator or a repressor of its target genes. Furthermore, SALL4 interacts with other partners to control the expression of many downstream genes and the activation of various key signaling transduction pathways. SALL4 is considered as a promising diagnostic and prognostic biomarker and therapeutic target for cancer. In this review, we highlighted the major advances in the roles and mechanisms of SALL4 in cancer and the therapeutic strategies for targeting SALL4 to treat cancer.

Abstract P2-18-02: Promoter hypomethylation associated upregulation of MEN1 mRNA expression and its correlation with pathological parameters in Indian breast cancer patients

Abstract Background: Breast cancer in the recent years has accounted to be most frequently reported cancer across the globe. Nearly 11.7% of total cancer cases were of breast cancer and 6,84,996 deaths were reported in the year 2020. Multiple endocrine neoplasia type 1 gene that encodes for menin protein is known be involved in numerous signaling pathways and is also reported to show its interactions with histone modifiers. MEN1 is frequently reported to be dysregulated in the cancer including neuroendocrine tumors, lung cancer and melanoma. However, the role of MEN1 in case of Breast cancer has not been well understood. Lifestyle, environmental conditions and ethnicity play crucial role in epigenetic modulation of gene expression. In the current scenario with high increase in number of cancer cases, there is need to develop more personalized course of treatment rather than generalized approach. Thus, discovery of new biomarkers will aid in designing better diagnostic and therapeutic strategy to treat cancer. Aims and Objective: In this study we aim to find MEN1 mRNA expression and its connection with the MEN1 promoter methylation in case of Indian breast cancer patients and to correlate our findings with the pathological parameters of the patients to understand the role of MEN1 gene in breast cancer progression. Material and methods: The ethical approval for the study was procured from Institutional ethical committee of AIIMS,New Delhi and Jamia Millia Islamia, New Delhi. The study comprises of 44 pair of Breast tissue samples including cancer and adjacent normal tissue collected at department of surgical oncology AIIMS, New Delhi and were stored in RNA later and PBS at -80˚C for RNA and DNA extraction respectively. DNA was extracted through PCI (Phenol-Chloroform-Isoamyl alcohol) method and was further confirmed by Agarose gel electrophoresis. TRIZOL method was used to extract RNA from tissue samples and was quantified using nanodrop. Moreover, cDNA synthesis was carried out using Verso cDNA synthesis kit. To investigate the MEN1 mRNA expression, RT- PCR was carried out with LightCycler96 SYBR Green I Master (Roche) using specific primers. To analyze the promoter methylation status of MEN1 promoter region, CT- conversion was done and MS-PCR was performed using Methylation and Unmethylation specific primers. Statistical analysis was done using Graph Pad and SPSS to correlate our findings with clinical parameters. Results: In our study we found 27 out of 44 patients to exhibit up-regulation of MEN1 mRNA in the breast cancer tissue as compared with the normal tisuue. MEN1 promoter unmethylation was detected in 25 out of 44 cases, which revealed its significant correlation with the upregulated MEN1 gene. Further on correlation of our data with the clinical parameters, we found its significant association with the estrogen receptor status and age of menopause of the patients. Conclusion: Our results of the MEN1 mRNA expression study and its association with MEN1 promoter methylation in case of breast cancer suggests the tumorigenic role of MEN1 in breast cancer. Our findings thereby indicate the possible role of MEN1 gene in progression of the disease. Further study on large sample size will aid in better understanding the role of MEN1 gene in Breast carcinoma. Citation Format: Sheersh Massey, Aasif Khan, Asifa Khan, SVS Deo, Syed Akhtar Husain. Promoter hypomethylation associated upregulation of MEN1 mRNA expression and its correlation with pathological parameters in Indian breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-18-02.

Epigenetics and the role of nutraceuticals in health and disease.

In the post-genomic era, the data provided by complete genome sequencing could not answer several fundamental questions about the causes of many noninfectious diseases, diagnostic biomarkers, and novel therapeutic approaches. The rapidly expanding understanding of epigenetic mechanisms, as well as widespread acceptance of their hypothesized role in disease induction, facilitated the development of a number of novel diagnostic markers and therapeutic concepts. Epigenetic aberrations are reversible in nature, which enables the treatment of serious incurable diseases. Therefore, the interest in epigenetic modulatory effects has increased over the last decade, so about 60,000 publications discussing the expression of epigenetics could be detected in the PubMed database. Out of these, 58,442 were published alone in the last 10years, including 17,672 reviews (69 historical articles), 314 clinical trials, 202 case reports, 197 meta-analyses, 156 letters to the editor, 108 randomized controlled trials, 87 observation studies, 40 book chapters, 22 published lectures, and 2 clinical trial protocols. The remaining publications are either miscellaneous or a mixture of the previously mentioned items. According to the species and gender, the publications included 44,589 human studies (17,106 females, 14,509 males, and the gender is not mentioned in the remaining papers) and 30,253 animal studies. In the present work, the role of epigenetic modulations in health and disease and the influencing factors in epigenetics are discussed.

Egg white protein hydrolysate decreased blood pressure via the competing endogenous RNA regulatory networks in female spontaneously hypertensive rats.

Despite numerous studies having reported the effects and mechanisms of antihypertensive peptides including peptides derived from egg white proteins, the role of peptides in a female hypertensive animal model is unknown. On the other hand, the role of epigenetic modulation by peptide treatment has rarely been investigated. This study sought to investigate the effect of egg white protein hydrolysate (EWH) in female spontaneously hypertensive rats (SHRs) as well as to explore the underlying mechanisms from the perspectives of the transcriptome and the profiles of non-coding RNAs. Young (12-14-week-old) female SHRs were orally administered 250 mg per kg body weight (low-dose) or 1000 mg per kg body weight (high-dose) EWH daily for 10 weeks. The blood pressure of the rats was monitored weekly. The mRNA and non-coding RNAs (miRNA, lncRNA, and circRNA) in the aorta were profiled by the high-throughput RNA-seq technique. Differentially expressed (DE) RNAs in the aorta were identified for the construction of the competing endogenous RNA (ceRNA) networks and key molecules were validated by qRT-PCR. The treatment of the high-dose EWH showed a significant effect on reducing blood pressure in female SHRs. Bioinformatic analyses revealed 813, 90, 347 and 869 DE-mRNAs, DE-miRNAs, DE-lncRNAs and DE-circRNAs, respectively. The CNTN5-LncRNA-XR_001835895.1-miR-384-5p was identified as the central network which was validated in the aorta and circulation of female SHRs. The results from this study demonstrated that the treatment with EWH reduced blood pressure via regulating the ceRNA networks in female SHRs, which provided novel insights into the mechanisms of food protein-derived antihypertensive peptides.

The two faces of DNA oxidation in genomic and functional mosaicism during aging in human neurons.

Maintaining genomic integrity in post-mitotic neurons in the human brain is paramount because these cells must survive for an individual’s entire lifespan. Due to life-long synaptic plasticity and electrochemical transmission between cells, the brain engages in an exceptionally high level of mitochondrial metabolic activity. This activity results in the generation of reactive oxygen species with 8-oxo-7,8-dihydroguanine (8-oxoG) being one of the most prevalent oxidation products in the cell. 8-oxoG is important for the maintenance and transfer of genetic information into proper gene expression: a low basal level of 8-oxoG plays an important role in epigenetic modulation of neurodevelopment and synaptic plasticity, while a dysregulated increase in 8-oxoG damages the genome leading to somatic mutations and transcription errors. The slow yet persistent accumulation of DNA damage in the background of increasing cellular 8-oxoG is associated with normal aging as well as neurological disorders such as Alzheimer’s disease and Parkinson’s disease. This review explores the current understanding of how 8-oxoG plays a role in brain function and genomic instability, highlighting new methods being used to advance pathological hallmarks that differentiate normal healthy aging and neurodegenerative disease.

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.

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.

P5403Platelet lncRNA and mRNA: unravelling the role of epigenetic modulation in acute coronary syndrome

Abstract Background Platelets (PLT) play a pivotal role in thrombosis that represents the key event of acute coronary syndrome (ACS). Long noncoding RNA (lncRNA) are transcripts of more than 200 nucleotides not encoding for proteins and they are a challenging class of epigenetic regulators. As PLT are anucleated cellular fragments, they represent an ideal scenario to unlock ncRNAs undiscovered functions. In diabetic metabolic setting, PLT switch to a hyper-reactive phenotype, enhancing thrombotic risk of these subjects. As diabetes leads to macro and microvascular complications, lncRNA profile may unlock mechanism leading to pro-thrombotic milieu. Purpose Although PLT transcriptome and proteome have been widely investigated, only little is known about PLT lncRNA asset. Our pilot study aimed to assess how diabetes influences PLT coding and noncoding RNA in ACS. Methods Microarray analysis was performed on PLT RNA from three groups of patients (pts): 3 non-diabetic pts with not ST elevation (NSTE) ACS (ND-NSTE); 3 diabetic pts with NSTE (T2DM-NSTE) and 3 healthy controls (CTRL). We considered as significant RNA transcripts, those with a threshold of fold change >2 and p<0.05. Results Global transcriptomic analyses detected 20.642 lncRNAs and 18.949 mRNAs. We found significant dysregulation between T2DM-NSTE and ND-NSTE vs CTRL according to mRNA and lncRNA transcripts. Among the top ranked coding transcripts, mitochondrial-derived mRNAs, (ALAS, AHSP), were differentially expressed compared to CTRL. In addition, mRNAs linked to oxygen transport (HBG, HBA), PLT activation (SLC4A1), microparticles machinery (CORO6), calcium-homeostasis (CISD2), immune-thrombosis, apoptosis (APOPT1, EIF2AK2, IFI-6), cellular commitment (NOTCH3) related pathways were differently modulated. We identified a huge number of lncRNAs in PLT. Among them Linc ENSTehz746.03620452053 is a long intergenic noncoding RNA that could be involved in modulation of PI3K/AKT pathway, a central node for PLT activities Different expressed mRNA Volcano Plot Conclusion Our platelet-derived RNA template pilot study confirms the central role of PLT in ACS and shows a potential role of lncRNAs, as master of the epigenetic control. As we found the main difference of expression between ND-NSTE vs T2DM-NSTE groups, our data show the critical role of diabetes in the transcriptional setting of ACS.

Discovery of vanadium complexes bearing tridentate schiff base ligands as novel LSD1 inhibitors

Lysine specific demethylase (LSD1) plays a pivotal role in epigenetic modulation of gene expression. Abberrant expression of LSD1 was associated with the progress and oncogenesis of multiple human cancers. Herein, we report the preliminary anti-LSD1 evaluation of the synthetic vanadium (V) complexes. Among them, complex 2 showed a moderate inhibitory effect against LSD1 with IC50 value of 19.0 μM, as well as good selectivity over MAO-A/B. Complex 2 is the first vanadium based LSD1 inhibitor, which provides a novel scaffold for the development of LSD1 inhibitor.

Abstract A173: Long-term responders to epigenetic modulators: abexinostat and pazopanib

Abstract Characterization of long-term responders in a phase I trial evaluating the role of epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods: Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Histone acetylation and HDAC2 expression were correlated long-term responders, >1y). Results: Fifty-one patients including RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Toxicities and PK studies were reported previously. 7 pts had response > 23 months (23-60+), including 5/22 patients with RCC, and one patient with medullary thyroid and thymic neurondocrine cancer. Long-term response was associated with high HDAC2 expression in PBMCs, increased histone acetylation, and modulation of VEGF level. Conclusion: Epigenetic modulation with HDAC inhibitors is strongly dependent on host factors to promote long-term benefit to abexinostat and pazopanib in pretreated patients. Citation Format: Rahul Aggarwal, Nela Pawlowsk, Jennifer Grabowsky, Armand Harb, Kamran Abri-Lavasani, Scott Thomas, Pamela N. Munster. Long-term responders to epigenetic modulators: abexinostat and pazopanib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A173.

Porphyromonas gingivalis lipopolysaccharide stimulation in human periodontal ligament stem cells: role of epigenetic modifications to the inflammation.

Periodontitis is a chronic oral inflammatory disease produced by bacteria. Gingival retraction and bone and connective tissues resorption are the hallmarks of this disease. Chronic periodontitis may contribute to the risk of onset or progression of neuroinflammatory pathological conditions, such as Alzheimer’s disease. The main goal of the present study was to investigate if the role of epigenetic modulations is involved in periodontitis using human periodontal ligament stem cells (hPDLSCs) as an in vitro model system. hPDLSCs were treated with lipopolysaccharide of Porphyromonas gingivalis and the expression of proteins associated with DNA methylation and histone acetylation, such as DNMT1 and p300, respectively, and inflammatory transcription factor NF-kB, were examined. Immunofluorescence, Western blot and next generation sequencing results demonstrated that P. gingivalis lipopolysaccharide significantly reduced DNA methylase DNMT1, while it markedly upregulated the level of histone acetyltransferase p300 and NF-kB in hPDLSCs. Our results showed that P. gingivalis lipopolysaccharide markedly regulate the genes involved in epigenetic mechanism, which may result in inflammation induction. We propose that P. gingivalis lipopolysaccharide-treated hPDLSCs could be a potential in vitro model system to study epigenetics modulations associated with periodontitis, which might be helpful to identify novel biomarkers linked to this oral inflammatory disease.

Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer.

Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.

Is there any therapeutic value for the use of histone deacetylase inhibitors for chronic pain?

Chronic pain is a complex clinical condition that reduces the quality of life for billions of people. In recent years, the role of epigenetic modulation in the control of long-term neuronal plasticity has attracted the attention of pain researchers. The epigenetic mechanisms include covalent modifications of DNA and/or histone proteins. Mounting evidence suggests that the activity of histone deacetylases (HDACs) and levels of histone acetylation are dynamic and that these enzymes modulate pain-related synaptic plasticity. Therefore, HDACs play essential roles in chronic pain development and maintenance. In this mini review, we will discuss the role of HDACs in the pathogenesis of chronic pain and will consider the therapeutic value of HDAC inhibitors in treating chronic pain.

Role of epigenetic modulation in hypobaric hypoxia induced memory impairment

Event Abstract Back to Event Role of epigenetic modulation in hypobaric hypoxia induced memory impairment Rahul Kumar1, Vishal Jain2, Neetu Kushwah1, Aastha Dheer1, Dipti Prasad1 and Shashi B. Singh1* 1 Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurobiology Department, India 2 Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurophysiology Department, India Long term memory formation requires a series of cellular as well as molecular adaptation that control the gene expression at the transcription level. However, epigenetic mechanisms such as histone acetylation, methylation, phosphorylation and DNA methylation have emerge critical regulators of transcription during memory consolidation process. Epigenetic mechanism controls gene expression bidirectional i.e. either enhance or repress gene expression. In addition, histone acetylation has been the main mechanism of epigenetics and play important role in memory formation as well as reconsolidation. Stressful environmental conditions such as hypobaric hypoxia (HH) leads to change in learning and memory. Present study is designed to explore global as well as specific histone modifications, mainly acetylation in different brain regions during different duration of HH exposure. Sprague Dawley rats (220 to 230 gm) were exposed to different duration of HH i.e. 1, 3, 7 and 14 days in an animal decompression chamber at an altitude of 25,000 feet. After exposure, rats were sacrificed and hippocampus and cortex were isolated. Activity of histone acetylase (HAT), histone deacetylase (HDAC) and DNA methyl transferase (DNMT) was analyzed using kits. Further specific histone acetylation sites i.e. H2BK5Acetylation, H3K9Acetylation and H4K14Acetylation were also studied in different brain regions. Results from the present study revealed the correlation between expressions of HDAC and HIF-1 alpha which further control other hypoxia responsive genes in both the brain regions. Gradual increased expression of HDAC on HH exposure causes repression of learning and memory related genes. In addition, the decline in H2BK5Ac expression may also account for inactivation of transcription of memory responsive gene leading to decline in memory. In brief, it can be concluded that epigenetic modification at histone acetylation sites may account for HH mediated memory impairment. Keywords: Memory, epigenetic, in vivo, histone acetylation, hypobaric hypoxia Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Kumar R, Jain V, Kushwah N, Dheer A, Prasad D and Singh SB (2016). Role of epigenetic modulation in hypobaric hypoxia induced memory impairment. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00191 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Shashi B Singh, Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurobiology Department, New Delhi, North Delhi, India, drshashisingh@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Google Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Google Scholar Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh PubMed Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The Role of Epigenetic Modulation in the Cellular Response to Ionizing Radiation

More and more evidence demonstrate that epigenetic modulation plays important roles in many cellular processes and carcinogenesis. It also showed that epigenetic changes are involved in the cellular response to ionizing radiation. In current review, we will discuss the radiation-induced epigenetic modifications including DNA methylation changes, chromatin remodelling and alterations in microRNA expression, and their roles in the cellular response to ionizing radiation. The aim is to help understand the mechanisms underlying the radiation induced biological effects in cells and to find the future research interests.

Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease.

Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of various diseases, including kidney diseases. In the present article, we review the current data regarding the role of epigenetic modulation in chronic kidney disease (CKD) and kidney fibrosis, including DNA methylation and histone modification. Especially we focused on the role of transcription factors in epigenetic modulation and the possibility of therapeutic target of CKD. We have recently reported that transcription factor Kruppel-like factor 4 (also known as gut-enriched Kruppel-like factor) is expressed in kidney podocytes (visceral epithelial cells) and modulates podocyte phenotype by gene-selective epigenetic control. Targeting transcription factors for epigenetic modification may be a good candidate for remission and regression of CKD. It is necessary for the therapy of CKD with an epigenetic-based approach to investigate organ-, tissue-, or gene-specific treatment methods for reduction of side effects.

Role of Epigenetic Modulation for the Treatment of Sarcoma

Sarcoma is a disease that includes many different subtypes that can present with a wide range of differing clinical findings, prognosis, and treatment options. For certain subsets (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, gastrointestinal stromal tumor [GIST]), extensive clinical trials have delineated effective treatment regimens often involving combination therapy, including surgery, radiation, systemic chemotherapy, and small molecular inhibitors of tyrosine kinases (as in the case of GIST). For nearly all patients with sarcoma who have relapsed or developed metastasis, the therapeutic benefit of chemotherapy has reached a plateau and as such new treatment approaches are needed to move this field forward. We recommend that all patients have the opportunity to participate in clinical trials where available. Recently, in our clinic we have started to increase our use of molecular testing and DNA sequencing studies to help identify potential treatment options for patients. One area of evolving basic and clinical research in sarcomas is the field of epigenetic therapeutics. The enclosed article reviews the basics of epigenetics and highlights some completed and ongoing clinical trials of epigenetic treatments in sarcoma. We anticipate in the future that diagnostic platforms will be developed to help clinicians determine if an epigenetic therapy could be effective for an individual patient with sarcoma.