Virtual screening of natural bioactives in combating cancer through epigenetic modulation

2011 ◽  
Vol 1 (5) ◽  
pp. 12-16
Author(s):  
Ravi Kapopara ◽  
S. Prasanth Kumar ◽  
S K Patel ◽  
D K Sadhu ◽  
Y T Jasrai ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Histone H3 ◽  
Genetic Material ◽  
Dna Methyltransferases ◽  
Methyl Transferase ◽  
Computational Screening ◽  
Histone Deacetylase 8 ◽  
Epigenetic Events ◽  
Altered Gene ◽  
Epigenetic Modulation

Epigenetic events are due to altered gene expression without any changes inthe genetic material and characteristic of heritability via cell division. Theimpact of epigenetic control over cancer is one among the thrust area ofresearch in cancer biology. The present study deals about the virtual screeningof plant derived bioactives, directed against the key molecular regulatorsof the epigenetic events viz. DNA methyltransferases (DNMT1, DNMT2 andDNMT3B), Histone acetyltransferase (HAT), Histone deacetylase 8 (HDAC8),Histone H3 lysine 27 methyl transferase (H3K27MT) and Histone H3 specificlysine 4 demethylase (H3K4DM). This computational screening identifies themost efficient binders with respect to individual targets in terms of ligandbinding energy. The structure optimization of the best scored docked conformationswill be helpful to reveal new insights and development of naturalbioactives to combat cancer.

scholarly journals Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

2021 ◽  
Vol 22 (7) ◽  
pp. 3735
Author(s):  
Guillaume Velasco ◽  
Damien Ulveling ◽  
Sophie Rondeau ◽  
Pauline Marzin ◽  
Motoko Unoki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Catalytic Domain ◽  
De Novo ◽  
Mutation Screening ◽  
Histone H3 ◽  
Regulatory Elements ◽  
Germline Mutations ◽  
Dna Methyltransferases ◽  
Mendelian Disorders ◽  
Epigenetic Machinery

DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

scholarly journals Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2719
Author(s):  
Alba Loras ◽  
Cristina Segovia ◽  
José Luis Ruiz-Cerdá
Keyword(s):  
Bladder Cancer ◽  
Cancer Biology ◽  
Metabolic Regulation ◽  
Tumor Development ◽  
Dna Methyltransferases ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Invasive Approach ◽  
Non Invasive

Bladder cancer (BC) represents a clinical, social, and economic challenge due to tumor-intrinsic characteristics, limitations of diagnostic techniques and a lack of personalized treatments. In the last decade, the use of liquid biopsy has grown as a non-invasive approach to characterize tumors. Moreover, the emergence of omics has increased our knowledge of cancer biology and identified critical BC biomarkers. The rewiring between epigenetics and metabolism has been closely linked to tumor phenotype. Chromatin remodelers interact with each other to control gene silencing in BC, but also with stress-inducible factors or oncogenic signaling cascades to regulate metabolic reprogramming towards glycolysis, the pentose phosphate pathway, and lipogenesis. Concurrently, one-carbon metabolism supplies methyl groups to histone and DNA methyltransferases, leading to the hypermethylation and silencing of suppressor genes in BC. Conversely, α-KG and acetyl-CoA enhance the activity of histone demethylases and acetyl transferases, increasing gene expression, while succinate and fumarate have an inhibitory role. This review is the first to analyze the interplay between epigenome, metabolome and cell signaling pathways in BC, and shows how their regulation contributes to tumor development and progression. Moreover, it summarizes non-invasive biomarkers that could be applied in clinical practice to improve diagnosis, monitoring, prognosis and the therapeutic options in BC.

scholarly journals Epigenetic Effects Induced by Methamphetamine and Methamphetamine-Dependent Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-28 ◽  
Author(s):  
Fiona Limanaqi ◽  
Stefano Gambardella ◽  
Francesca Biagioni ◽  
Carla L. Busceti ◽  
Francesco Fornai
Keyword(s):  
Molecular Mechanisms ◽  
Neuropsychiatric Disorders ◽  
Behavioral Alterations ◽  
Neuronal Phenotype ◽  
Cellular Events ◽  
Epigenetic Effects ◽  
Molecular Events ◽  
Epigenetic Events ◽  
Genetic Modifications ◽  
Altered Gene

Methamphetamine is a widely abused drug, which possesses neurotoxic activity and powerful addictive effects. Understanding methamphetamine toxicity is key beyond the field of drug abuse since it allows getting an insight into the molecular mechanisms which operate in a variety of neuropsychiatric disorders. In fact, key alterations produced by methamphetamine involve dopamine neurotransmission in a way, which is reminiscent of spontaneous neurodegeneration and psychiatric schizophrenia. Thus, understanding the molecular mechanisms operated by methamphetamine represents a wide window to understand both the addicted brain and a variety of neuropsychiatric disorders. This overlapping, which is already present when looking at the molecular and cellular events promoted immediately after methamphetamine intake, becomes impressive when plastic changes induced in the brain of methamphetamine-addicted patients are considered. Thus, the present manuscript is an attempt to encompass all the molecular events starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons to explain how specific neurotransmitters and signaling cascades produce persistent genetic modifications, which shift neuronal phenotype and induce behavioral alterations. A special emphasis is posed on disclosing those early and delayed molecular events, which translate an altered neurotransmitter function into epigenetic events, which are derived from the translation of postsynaptic noncanonical signaling into altered gene regulation. All epigenetic effects are considered in light of their persistent changes induced in the postsynaptic neurons including sensitization and desensitization, priming, and shift of neuronal phenotype.

scholarly journals Histone H1 prevents non-CG methylation-mediated small RNA biogenesis in Arabidopsis heterochromatin

2021 ◽  
Author(s):  
Jaemyung Choi ◽  
David Bruce Lyons ◽  
Daniel Zilberman
Keyword(s):  
Dna Methylation ◽  
Transposable Elements ◽  
Small Rna ◽  
Histone H3 ◽  
Histone H1 ◽  
Dna Methyltransferases ◽  
Flowering Plants ◽  
Genomic Sequences ◽  
Rna Molecules ◽  
Rna Biogenesis

Flowering plants utilize small RNA molecules to guide DNA methyltransferases to genomic sequences. This RNA-directed DNA methylation (RdDM) pathway preferentially targets euchromatic transposable elements. However, RdDM is thought to be recruited by methylation of histone H3 at lysine 9 (H3K9me), a hallmark of heterochromatin. How RdDM is targeted to euchromatin despite an affinity for H3K9me is unclear. Here we show that loss of histone H1 enhances heterochromatic RdDM, preferentially at nucleosome linker DNA. Surprisingly, this does not require SHH1, the RdDM component that binds H3K9me. Furthermore, H3K9me is dispensable for RdDM, as is CG DNA methylation. Instead, we find that non-CG methylation is specifically required for small RNA biogenesis, and without H1 small RNA production quantitatively expands to non-CG methylated loci. Our results demonstrate that H1 enforces the separation of euchromatic and heterochromatic DNA methylation pathways by excluding the small RNA-generating branch of RdDM from non-CG methylated heterochromatin.

scholarly journals The Significance of Chromosome 11 Abnormalities in Patients with AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4451-4451
Author(s):  
Anna Przybylowicz-Chalecka ◽  
Joanna Czerwinska-Rybak ◽  
Blazej Ratajczak ◽  
Zuzanna Kandula ◽  
Andrzej Szczepaniak ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Gene Rearrangement ◽  
Negative Impact ◽  
Laboratory Data ◽  
Genetic Material ◽  
Normal Karyotype ◽  
Molecular Techniques ◽  
Fish Analysis ◽  
Chromosome 11 ◽  
Fish Method

Abstract Introduction: At the time of diagnosis AML the finding of KMT2A gene rearrangement qualifies patient to the group with adverse cytogenetic risk according to ELN 2017. In many hematooncological diseases including AML abnormalities concerning another regions of chromosome 11 are detected. However, their significance for outcome, CR rate, OS is still unknown. The main aim of this study was analysis of chromosome 11 abnormalities in AML patients, focusing on these without KMT2A gene rearrangement and its influence on patients outcome. Methods: Karyotype analysis from bone marrow aspirate was performed for patients with chromosome 11 abnormalities (abn11, n=36) and compared to two groups: with complex (CK, n=20) and normal karyotype (NK, n=44). The basic clinical and laboratory data including cytogenetic (karyotype and FISH method) and presence of TP53 deletion were analyzed to characterize in detail the group of patients with chromosome 11 abnormalities. Patients were treated with intensive chemotherapy, in 33% of them allogeneic cell transplantation (alloHCT) was performed. Results: In patients with abn11 the most frequent type of aberration was translocation, 11q23(+)/KMT2A(-) and 11q10-25 as a main region involved in aberrations, with minimal narrowing of region to 11q22. In patients with abn11 and translocation (excluding t(9;11)) there was higher frequency occurrence of 1 to 2 additional abnormalities (p=0.033) and lower frequency of complex karyotype existence (p=0.026). The gain of genetic material from chromosome 11 was observed in 33% of patients with abn11 group and the minimal amplified region was 11q22. Furthermore, in patients with amplification of chromosome 11 region, different additional cytogenetic abnormalities (such as monosomy 5 (p=0.045) and 18 (p<0.001)) were found in comparison to patients with other abnormalities of chromosome 11. Additional KMT2Agene copies were often observed in patients with 11q10-25 (p=0.013) and 11pter-qter (p=0.022) region involvement. The lowest frequency of TP53 deletion was in NK group (p=0.002) but comparable in patients with CK and abn11 without impact on OS and CR. The FISH analysis did not revealed KMT2A gene rearrangement in group with normal karyotype. There was particular attention to 11q23 region in patients with AML which enabled abnormality detection in GTG analysis, furthermore KMT2A rearrangement was confirmed or excluded by FISH method. In few cases FISH analysis allowed verification of KMT2A gene status in case of atypical hybrydization pattern occurrence. Leukocyte counts (p<0.001) and type of AML (de novo, secondary, therapy-related, p=0.022) differs in patients with abn11 in comparison to remained studied subgroups (Table 1.). The lowest blast percentage was observed in patients with 11p rearrangement (p=0.045). There were no significant differences in OS between all 3 groups of patients. CR was achieved in 15% in a CK group and it was significantly lower than in NK and abn11 group (p<0.001). Furthermore alloHCT improve OS in all treated patients (p<0.001). Additional genetic material from chromosome 11 occurrence had negative impact on OS (p<0.001) and CR (p=0.007). Patients with abn11 who achieved CR had lower median age (p=0.01) compared to these without CR. The lowest percentage of CR in abn11 group was observed in patients with additional KMT2A gene copies (p=0.008), 11q10-25 region involvement (p=0.036), HSR (homogeneously staining region) and aneuploidy (p=0.04). Conclusions: In summary, the most frequent region involved in chromosome 11 aberration was 11q22. Additional material derived from chromosome 11 had negative impact on CR and OS. Cytogenetic and molecular analysis in patients with AML are needed to detect most of abn11. In the era of targeted therapies their identification is very important to qualify the patient for more effective treatment. Both cytogenetic and molecular techniques widespread knowledge about cancer biology, however, classic cytogenetic is still "gold standard" and crucial method in AML diagnosis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Richa Pant ◽  
Priyanka Firmal ◽  
Vibhuti Kumar Shah ◽  
Aftab Alam ◽  
Samit Chattopadhyay
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Cancer Progression ◽  
Underlying Disease ◽  
Metabolic Health ◽  
Therapeutic Interventions ◽  
Tissue Mass ◽  
Epigenetic Events ◽  
Adipocyte Hypertrophy ◽  
Altered Gene

Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals’ genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.

Physical and Functional Association of PLZF with Histone Methyl Transferase and Histone Demethylase.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 731-731
Author(s):  
Itsaso Hormaeche ◽  
Kim Rice ◽  
Joti Marango ◽  
Fabien Guidez ◽  
Arthur Zelent ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Histone H3 ◽  
Promyelocytic Leukemia ◽  
Gene Repression ◽  
Histone Demethylases ◽  
Methyl Transferase ◽  
Histone Methyl Transferase

Abstract The promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor fused to RARα in the t(11;17) translocation associated with retinoic acid resistant acute promyelocytic leukemia (APL). As a result of this chromosomal abnormality, two oncogenic proteins are produced, PLZF-RARα and RARα-PLZF. Wild type PLZF is expressed in CD34+ progenitor cells and declines during differentiation. PLZF is a tumor suppressor that causes cell cycle arrest, downregulating genes such as cyclinA2 and c-myc. We previously showed that transcriptional repression by PLZF is mediated by the recruitment of histone deacetylases to target genes, this being critical for its ability to control growth and affect RAR target genes. We now show that PLZF alters the methylation state of histones in its target genes. A biotinylated form of PLZF co-purified in cells along with a histone methyl transferase (HMT) activity for native histones. Using mutant histone H3 tail peptides, we showed that this activity methylated histone H3 on lysine 9 (H3K9me). Tagged forms of PLZF as well as endogenous PLZF co-precipitated in vivo with G9a histone methyl transferase, an enzyme that can mono and dimethylate H3K9 in euchromatin subject to gene repression. The interaction of PLZF with G9a required the presence of the N-terminal BTB/POZ domain as well as a second, more C-terminal, repression domain of PLZF. Given the newly found role of active histone demethylation in gene control we also tested the interaction of PLZF with LSD1, an enzyme associated with gene repression that demethylates H3K4. As in the case of G9a, the interaction of PLZF with LSD1 required both repression domains, suggesting, that these proteins may be part of a multi-protein complex containing multiple contact points with PLZF. Expression of G9a or LSD1 augmented transcriptional repression mediated by PLZF on reporter genes, indicating a functional interaction between histone methylation modifiers and PLZF. To determine the ability of PLZF to affect chromatin methylation in vivo, a Gal4-PLZF fusion protein was expressed in cells containing a chromatin-embedded Gal4-tk-Luciferase reporter gene. In the presence of PLZF, a chromatin immunoprecipitation experiment showed an increase in H3K9 methylation of the target gene while H3K4 methylation decreased, consistent with the ability of PLZF to interact with LSD1 and G9a. Lastly we compared the ability of the histone modifying proteins to interact with the APL fusion proteins PLZF-RARα, PML-RARα and NPM-RARα. Co-precipitation experiments showed a robust interaction between PLZF-RARα and G9a and LSD1 while the PML-RARα and NPM-RARα fusions bound these proteins significantly less avidly. Collectively all these data indicate that specific histone methylation is an important mode of action of PLZF in gene repression. The retinoic acid resistance of t(11;17)-APL may be related to its ability to interact with HMTs and histone demethylases. Hence therapeutic targeting of HMTs and histone demethylases might be considered as a novel mode of therapy in APL and other hematological malignancies.

scholarly journals Balance between Acetylation and Methylation of Histone H3 Lysine 9 on the E2F-Responsive Dihydrofolate Reductase Promoter

2003 ◽  
Vol 23 (5) ◽  
pp. 1614-1622 ◽  
Author(s):  
Estelle Nicolas ◽  
Christine Roumillac ◽  
Didier Trouche
Keyword(s):  
Transcription Factor ◽  
Dihydrofolate Reductase ◽  
Histone H3 ◽  
Methyl Transferase ◽  
Pocket Proteins ◽  
Temporal Regulation ◽  
Spatial Regulation ◽  
E2f Transcription Factor ◽  
Histone Methyl Transferase ◽  
Related Proteins

ABSTRACT Epigenetic marks that specify silent heterochromatic domains in eucaryotic genomes include methylation of histone H3 lysine 9. Strikingly, active loci in the vicinity of silent domains are sometimes characterized by acetylation of histone H3 lysine 9, suggesting that the balance between these two competitive modifications is important for the establishment of specific chromatin structures. Some euchromatic genes, targeted by the retinoblastoma protein Rb, are also believed to be regulated by histone H3 lysine 9 methylation. Here, we study the dihydrofolate reductase promoter, which is repressed in G0 and at the beginning of G1 by p107 or p130, two Rb-related proteins. We found that these two pocket proteins share with Rb the ability to associate with the histone methyl transferase SUV39H1. SUV39H1 can be recruited to the E2F transcription factor and functions as a transcriptional corepressor. With ChIP assays followed by real-time PCR, we showed that K9 of histone H3 evolves from a hypermethylated state in G0 to a hyperacetylated state at the G1/S transition. Taken together, these results indicate that the temporal regulation of euchromatic promoters may involve controlling the balance between methylation and acetylation of histone H3 lysine 9, a feature previously described for the spatial regulation of chromatin function.

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