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Readers, writers and erasers

Scientific meeting

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Starts:

May
242017

09:00

Ends:

May
252017

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Satellite meeting organised by Professor A Ganesan, Professor Marianne Rots, Dr Paola Arimondo and Dr Akane Kawamura.

Nucleosome

Epigenetics refers to the control mechanisms that determine which genes are turned on or off in eukaryotic organisms. Epigenetics is fundamental to normal development and an organism’s response to the environment while its dysregulation is linked to disease conditions. This interdisciplinary meeting brought together chemists and biologists that are internationally leading in cutting edge areas of epigenetics.

Speaker biographies and abstracts are available below. Recorded audio of the presentations will be available on this page shortly.

Attending this event

This event has taken place.

Prior to this meeting, there was a related discussion meeting 'Frontiers in epigenetic chemical biology' held at the Royal Society London on 22 - 23 May 2017.

Enquiries: Contact the Scientific Programmes team

Event organisers

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Schedule of talks

24 May

09:00-12:30

Session 1

4 talks Show detail Hide detail

Chairs

Professor Lucia Altucci, University of Campania Luigi Vanvitelli, Italy

09:05-09:30 Catalytic plasticity of DNA methyltransferases: can writers be erasers?

Professor Saulius Klimašauskas, Vilnius University, Lithuania

Abstract

Epigenetic states of cytosine, (5-methylcytosine (5mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine and 5-carboxylcytosine (caC)) are part of an intricate regulation in eukaryote genomes including humans, which contribute to normal phenotypic variation and disease risk. DNA cytosine-5 methyltransferases (C5-MTases), which catalyse the transfer of the methyl group from the ubiquitous cofactor AdoMet to the 5-position of cytosine residues, serve as primary writers of epigenetic DNA marks. Mechanistic studies of both bacterial and mammalian enzymes showed that the reaction requires covalent activation of the cytosine ring by the enzyme before the cofactor-dependent methylation can occur. The group found that, in the absence of AdoMet, the activated cytosine or hmc residues can react with non-cofactor-like compounds such as aldehydes or thiols leading to their further modification; similar enzymatic activation of hmC or caC residues leads to a loss of 5-hydromethyl- or 5-carboxyl groups, respectively, yielding unmodified cytosine in DNA. These novel atypical reactions illustrate a high catalytic plasticity of C5-MTases in vitro and provide plausible chemical precedents in support of possible roles of these enzymes in direct erasure of epigenetic marks in mammalian DNA.

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09:30-09:45 Discussion

09:45-10:15 Sympathy for the methyl: a 'library-on-library' screening approach to identify small-molecule ligands of methyl-lysine reader proteins

Professor Gianluca Sbardella, University of Salerno, Italy

Abstract

The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. Using a library of biotin-tagged analogs the group screened a protein domain microarray of methyl-lysine effector molecules to rapidly detect compounds with novel binding profiles – either improved or loosened specificity. Using this approach, the group identified compounds that acquired novel interactions with Tudor domain-and MBT domain-containing proteins.

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10:15-10:30 Discussion

10:30-11:00 Coffee

11:00-11:30 Development of cyclic peptide inhibitors against KDM4 JmjC histone demethylases

Dr Akane Kawamura, University of Oxford, UK

Abstract

Post-translational modifications on histone tails are important in epigenetic regulation of gene expression. N-methylation on lysine residues is removed by histone demethylases (KDMs). JmjC-domain containing KDMs are Fe(II) and 2-oxoglutarate dependent oxygenases, which make up the larger of the two KDM families. This talk will give an overview of our recent inhibitor development efforts for this family of enzymes, including new strategies used to develop histone substrate competitive cyclic peptide inhibitors for the KDM4A-C.

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11:30-11:45 Discussion

11:45-12:15 Chemical epigenetics - inhibitors of methyl lysine readers and sirtuin deacylases

Professor Manfred Jung, University of Freiburg, Germany

Abstract

Professor Jung's research focus is `Chemical Epigenetics´ and deals with the development and application of chemical and biochemical tools to dissect biological pathways, to validate therapeutic targets and to discover and optimise potential drugs addressing a wide range of epigenetic targets. In this talk two targets are presented: NAD-dependent protein deacetylases (sirtuins) and the methyl lysine reader protein Spindlin1 (Spin1). The group has developed a wide range of biochemical and biophysical assays for these targets which have identified new hits. These were subsequently optimised in a structure-guided fashion for potency and selectivity and were converted into functionalised tools for chemical biology. For example, the group has developed a biotinylated Sirt2 inhibitor for chemoproteomic studies and a proteolysis targeted chimera (PROTAC) based on thalidomide and Sirt2 inhibitors from the SirReal class.

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12:15-12:30 Discussion

12:30-13:30

Lunch

13:30-17:15

Session 2

4 talks Show detail Hide detail

Chairs

Dr Akane Kawamura, University of Oxford, UK

13:30-14:00 Targeting the lysine specific demethylase LSD1

Professor A. Ganesan, University of East Anglia, UK

Abstract

For a long time, the methylation of lysine residues in proteins was considered an irreversible process. Over the last decade, this viewpoint has dramatically changed with the discovery of lysine demethylase enzymes (KDMs). The KDMs are evolutionarily conserved between eukaryotic species and subdivided into lysine-specific demethylases (LSD1 and LSD2) and the Jumonji C demethylases (over 20 human isoforms). LSD1, the first identified demethylase in 2004, performs an essential function in normal growth and development. Nevertheless, human disease states are strongly linked to aberrant LSD1 activity. Through demethylation of H3K4 residues, LSD1 maintains stemness in leukaemia and silencing of differentiation while H3K9 demethylation promoted by the androgen or oestrogen receptor drives proliferation. Interest in LSD1 inhibition as a therapeutic strategy has matured over the last decade and led to multiple clinical candidates currently undergoing trials for cancer. The presentation will provide an overview of LSD1 function and medicinal chemistry and give examples of reversible and irreversible inhibitors from our research.

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14:00-14:15 Discussion

14:15-14:45 Targeting transcriptional programmes through disruption of BET complexes

Professor Panagis Filippakopoulos, University of Oxford, UK

Abstract

Transcriptional programs are often deregulated in disease, offering opportunities for therapeutic intervention. One of the most promising over recent years is through targeting epigenetic readers of the bromo and extra-terminal (BET) family. Despite the successful translation of BET-inhibitors into the clinic, emergence of toxicity and resistance necessitate better understanding of the underpinning biology, in order to develop safer therapeutics. To address this the group studied the contribution(s) of the modular domain organisation of BET proteins offering a recruitment platform for transcriptional complexes. Employing proteomics the group finds BETs linked to large complexes associated both with transcriptional activation as well as suppression of key survival programmes. The group furthermore identifies shared and distinct structural determinants leading to complex assembly and demonstrate in vitro and in cells that it is possible to target specific BET-complex component interactions leading to complex perturbation. These data point towards an under-appreciated role of modularity within BETs in linking transcriptional attenuators to chromatin, revealing protein-specific contributions into complex assembly and informing into potential combination therapies providing novel points for intervention in a clinical setting.

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14:45-15:00 Discussion

15:00-15:30 Tea

15:30-16:00 Transition state mimics as PRMT inhibitors and tools for structural studies

Professor Nathaniel I. Martin, Utrecht University, The Netherlands

Abstract

The protein arginine N-methyltransferases (PRMTs) are a family of enzymes that function by specifically transferring a methyl group from the cofactor S-adenosyl-L-methionine (AdoMet) to the guanidine moiety of arginine side chains in target proteins. Most notable is the PRMT-mediated methylation of arginine residues found in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors hold potential as a means of developing new therapeutics. The group here reports the synthesis and evaluation of a series of small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity was observed when testing these compounds against a panel of methyltransferases.

An atomic-scale understanding of the PRMT catalytic mechanism is also crucial for both fundamental biological and pharmacological applications. Despite intense efforts, crystal structures of PRMT complexes with long peptides and full-length substrates have not been solved due to their inherent instability. To address this issue the group has recently developed peptide-based transition state mimics that form stable complexes with the PRMT enzyme CARM1 resulting in high-resolution co-crystal structures. These findings provide an exciting new approach to understanding PRMT substrate recognition and the regulation of arginine methylation.

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16:00-16:15 Discussion

16:15-17:15 Selected short presentations

17:15-18:15

Poster session

25 May

09:00-12:40

Session 3

4 talks Show detail Hide detail

Chairs

Dr Paola B. Arimondo, CNRS ETaC, France

09:00-09:30 Epigenetic dysfunctions in cancer: a cause or a consequence?

Professor Bozena Kaminska, Nencki Institute of Experimental Biology, Poland

Abstract

The epigenetic landscape is deregulated in cancer due to aberrant activation/ inactivation of enzymes maintaining and modifying the epigenome. Aberrations at the global histone level and/or specific histone modifications may produce distorted patterns of gene expression and malfunction of proteins that regulate chromatin structure. Recent whole genome studies demonstrated that histones and chaperone proteins harbour mutations that may result in gross alterations of the epigenome leading to genome instability. IDH1/2 (isocitrate dehydrogenase 1/2) mutations have been detected in hematologic malignancies and certain solid tumours. Point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in accumulation of the D-2-hydroxyglutarate (D-2HG). High levels of D-2HG interfere with cellular metabolism and epigenetic regulation by inhibiting histone and DNA demethylases, which results in blocking cellular differentiation. Histone deacetylases (HDACs) are critical regulators of gene expression that promote chromatin changes by deacetylating histones. Aberrant regulation of HDACs contributes to malignant transformation and progression in many human cancers. Dysfunction of the histone lysine methyltransferase EZH2 occurs in numerous cancers. EZH2 a part of the polycomb repressive complex 2 which catalyses trimethylation of histone H3 lysine 27. It supports undifferentiated phenotype and blocks differentiation during embryonic development and carcinogenesis. Epigenetic-based mechanisms are reversible and 'resetting' the abnormal cancer epigenome by pharmacological compounds targeting epigenetic enzymes is a promising strategy. Several novel drugs targeting tumours with mutated IDH1/2/ and numerous HDAC inhibitors have been identified. These compounds cause cell cycle arrest or death, inhibit DNA repair and some entered clinical trials for cancer treatment.

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09:30-09:45 Discussion

09:45-10:15 Epigenetic biomarkers

Professor Carmen Jerónimo, Portuguese Oncology Institute and University of Porto, Portugal

Abstract

An increasing body of evidence is implicating several epigenetic mechanisms as driving forces of neoplastic transformation. Among these, aberrant DNA methylation is, by far, the most widely studied, followed by deregulated expression of chromatin machinery proteins and non-coding RNAs, including microRNAs. Importantly, cancer-related epigenetic alterations may provide novel cancer biomarkers, intended for early detection and diagnosis, assessment of prognosis, and prediction of response to therapy. The importance of early diagnosis in Oncology has been emphasised and although current methodologies (such as cytology, histopathology, immunohistochemistry, etc) play a critical role, molecular markers may complement or, eventually, replace them if more effective. Because epigenetic alterations often precede the emergence of the malignant phenotype, they are advantageous for early cancer detection. They might also be detected in clinical samples, including those obtained by biopsy, as well from those obtained by non-invasive methods, such as urine. Moreover, early detection of cancer relapse before it manifests clinically (or on imaging during routine patient follow-up) might be accomplished through epigenetic-based biomarkers. Some epigenetic alterations have also been associated with tumour behaviour and may, thus, serve as prognostic biomarkers. 

In this talk, Professor Jerónimo will focus on the major recent findings obtained by her research team regarding epigenetic mechanisms implicated in urological tumorigenesis as well as the potential usefulness of epigenetic-based biomarkers for detection and prognostication in these cancers. 


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10:15-10:30 Discussion

10:30-11:10 Coffee

11:10-11:40 Epigenome approaches for identification of treatment resistance in cancer

Professor Lucia Altucci, University of Campania Luigi Vanvitelli, Italy

Abstract

Aberrant activity of epigenetic enzymes plays a role in tumorigenesis. Reversal of these aberrant modifications has emerged as a strategy for cancer treatment. By applying epigenome-based patient stratification, the group identified a set of chromatin areas predictive for standard treatment resistance in leukaemias. Professor Altucci reports that a novel dual-epidrug, as effective in standard treatment resistant cancers. The group identified both the mechanistic insights of this action and biomarkers that might turn into a differential diagnostic tool for leukaemia patients. Together, the group provides proof of concept for the use of epigenome profiling coupled to epi-drugs to ‘personalise’ precision medicine.

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11:40-11:55 Discussion

11:55-12:25 Environmental metals, epigenetics and cardiovascular risk: a population-based perspective

Dr Maria Tellez-Plaza, Hospital Clinic of Valencia University, Spain; Johns Hopkins Bloomberg School of Public Health, USA

Abstract

Cardiovascular disease is a major cause of mortality and morbidity world-wide. Current algorithms for cardiovascular risk prediction, which combine behavioural, clinical, and biochemical markers, are, however, of limited accuracy. Understanding novel factors and mechanisms for cardiovascular disease development can contribute to the identification of at-risk individuals, who could benefit the most from preventive interventions. Non-essential environmental metals are emerging as major contributing factors to cardiovascular health in study populations exposed to low or moderate metal dose through air, food or water. Moreover, metals accumulate in the body where they can induce long-term damages. Dr Tellez-Plaza will be discussing available evidence in support of metals as environmental determinants of both epigenetic markers and cardiovascular disease in general populations. The identification of epigenomic regions that are environmentally regulated and may be involved in pathways related to cardiometabolic risk can enable the implementation of both population-based and personalised strategies for the control of cardiovascular disease in the population. Moreover, several lines of evidence suggest that environmental exposures can influence health outcomes in subsequent generations, due to epigenetic changes.  It is of interest, thus, to explore novel epigenetic approaches for prevention and treatment of disease, which may be relevant for future generations.

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12:25-12:40 Discussion

12:30-13:30

Lunch

13:40-17:00

Session 4

4 talks Show detail Hide detail

Chairs

Professor A. Ganesan, University of East Anglia, UK

13:40-14:10 Induction of new fungal natural products by epigenetic modifiers: a systematic approach

Dr Jose-Rubén Tormo, Fundacion MEDINA, Spain

Abstract

Fungal endophytes are known to produce a wide variety of secondary metabolites (SMs) involved in their adaptation and survival within higher plants. Plant-microbe interaction may influence the expression of some biosynthetic pathways, otherwise cryptic in these fungi when grown in laboratory conditions. Epigenetic small-molecule modifiers of Histone Deacetylase (HDAC) and DNA methyltransferase (DNMT) activities have been successfully used to perturb the fungal secondary biosynthetic mechanisms, which has led to the induction of the expression of silent metabolite pathways. Adding epigenetic elicitors in fungal endophyte fermentations may induce the expression of biosynthetic pathways which may occur naturally in plant-microbe interaction.

The effects of 7 epigenetic modifiers will be described for a case study group of 13 fungal endophytes fermented during 7 and 14 days to evaluate the possible activation of silent biosynthetic pathways compared to their growth in standard conditions. The increase in production titers of global SMs profiles in some of the strains was slightly higher when the elicitors were present from that inoculum stage. Strains that produced differential SMs in presence of the small elicitors were studied in detail and their principal induced components identified and quantified by metabolomics.

The described use of epigenetic modifiers in a systematic approach ensured a successful generation of new SMs on regular basis. Current scale-up, purification and chemical characterisation of other selected strains/conditions will be described for the most promising new metabolites induced.



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14:10-14:25 Discussion

14:25-14:55 Dietary microbial metabolites as epigenetic modulators in health and disease

Dr Clarissa Gerhäuser, German Cancer Center, Germany

Abstract

Dietary agents from various sources target mechanisms involved in epigenetic gene regulation, including DNA methylation, histone modifications and noncoding RNAs. Recent research has indicated that gut microbial metabolites might be important mediators of these diet-epigenome interaction (Hullar MA, Fu BC. Cancer J 2014). Folate and B vitamins required to generate SAM for methylation reactions are provided by the gut microbiota. Phenolic acids generated by microbial degradation of dietary polyphenols inhibit DNMTs and HDAC activities. Berries and nuts are rich in ellagitannins, which are hydrolysed to ellagic acid and further microbially metabolised to urolithins. Whereas ellagitannin regulated the expression of small non-coding microRNAs, urolithins inhibit the activities or expression of HDACs and HATs in cultured cells. Glucosinolates from cooked cruciferous vegetables require gut bacterial thioglycosidases for cleavage to reactive isothiocyanates (ITCs). The diversity of the gut microbiome therefore affects the bioavailability of ITCs, which can be further metabolized to HDAC inhibitors. Fermentation of dietary fibre leads to formation of short chain fatty acids including butyrate. Butyrate has a dose-dependent dual effect on HATs and HDACs and both promotes proliferation and induces cell cycle arrest and differentiation Donohoe et al. Mol Cell 2012). Long-chain omega-3-fatty acids (LC ω-3-FA) regulate histone methylation and miRNA expression in vitro and in vivo. The availability and efficacy of LC ω-3 FA might be affected by gut microbial metabolism to conjugated linolenic acids (CLA), which were shown to modify methylation patterns of genes and expression of miRNAs involved in energy balance and lipid metabolism. In summary, these examples indicate that the gut microbiota interacts with the epigenome in various ways. Future studies need to integrate information on dietary intake, microbiome and metabolome, with genome-wide epigenetic profiling results to draw conclusions on how to influence this complex system in the direction of improved human health.

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14:55-15:10 Discussion

15:10-15:50 Tea

15:50-16:30 Selected short presentations

16:30-17:00 Concluding remarks

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Readers, writers and erasers Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ