Project acronym BACNK
Project Recognition of bacteria by NK cells
Researcher (PI) Ofer Mandelboim
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS6, ERC-2012-ADG_20120314
Summary NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.
Summary
NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.
Max ERC Funding
2 499 800 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym BRAINVISIONREHAB
Project ‘Seeing’ with the ears, hands and bionic eyes: from theories about brain organization to visual rehabilitation
Researcher (PI) Amir Amedi
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS5, ERC-2012-StG_20111109
Summary My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Summary
My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.
Max ERC Funding
1 499 900 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym CHOLINOMIRS
Project CholinomiRs: MicroRNA Regulators of Cholinergic Signalling in the Neuro-Immune Interface
Researcher (PI) Hermona Soreq
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary "Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Summary
"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."
Max ERC Funding
2 375 600 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym CLUE-BGD
Project Closing the Loop between Understanding and Effective Treatment of the Basal Ganglia and their Disorders
Researcher (PI) Hagai Bergman
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Advanced Grant (AdG), LS5, ERC-2012-ADG_20120314
Summary In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Summary
In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model).
This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys.
This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.
Max ERC Funding
2 476 922 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym DEATHSWITCHING
Project Identifying genes and pathways that drive molecular switches and back-up mechanisms between apoptosis and autophagy
Researcher (PI) Adi Kimchi
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS3, ERC-2012-ADG_20120314
Summary A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.
Summary
A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.
Max ERC Funding
2 500 000 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym DMR-CODE
Project Decoding the Mammalian transcriptional Regulatory code in development and stimulatory responses
Researcher (PI) Ido Amit
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary Transcription factors (TF) regulate genome function by controlling gene expression. Comprehensive characterization of the in vivo binding of TF to the DNA in relevant primary models is a critical step towards a global understanding of the human genome. Recent advances in high-throughput genomic technologies provide an extraordinary opportunity to develop and apply systematic approaches to learn the underline principles and mechanisms of mammalian transcriptional networks. The premise of this proposal is that a tractable set of rules govern how cells commit to a specific cell type or respond to the environment, and that these rules are coded in regulatory elements in the genome. Currently our understanding of the mammalian regulatory code is hampered by the difficulty of directly measuring in vivo binding of large numbers of TFs to DNA across multiple primary cell types and their natural response to physiological stimuli.
Here, we overcome this bottleneck by systematically exploring the genomic binding network of 1. All relevant TFs of key hematopoietic cells in both steady state and under relevant stimuli. 2. Follow the changes in TF networks as cells differentiate 3. Use these models to engineer cell states and responses. To achieve these goals, we developed a new method for automated high throughput ChIP coupled to sequencing (HT-ChIP-Seq). We used this method to measure binding of 40 TFs in 4 time points following stimulation of dendritic cells with pathogen components. We find that TFs vary substantially in their binding dynamics, genomic localization, number of binding events, and degree of interaction with other TFs. The analysis of this data suggests that the TF network is hierarchically organized, and composed of different types of TFs, cell differentiation factors, factors that prime for gene induction, and factors that bind more specifically and dynamically. This proposal revisits and challenges the current understanding of the mammalian regulatory code.
Summary
Transcription factors (TF) regulate genome function by controlling gene expression. Comprehensive characterization of the in vivo binding of TF to the DNA in relevant primary models is a critical step towards a global understanding of the human genome. Recent advances in high-throughput genomic technologies provide an extraordinary opportunity to develop and apply systematic approaches to learn the underline principles and mechanisms of mammalian transcriptional networks. The premise of this proposal is that a tractable set of rules govern how cells commit to a specific cell type or respond to the environment, and that these rules are coded in regulatory elements in the genome. Currently our understanding of the mammalian regulatory code is hampered by the difficulty of directly measuring in vivo binding of large numbers of TFs to DNA across multiple primary cell types and their natural response to physiological stimuli.
Here, we overcome this bottleneck by systematically exploring the genomic binding network of 1. All relevant TFs of key hematopoietic cells in both steady state and under relevant stimuli. 2. Follow the changes in TF networks as cells differentiate 3. Use these models to engineer cell states and responses. To achieve these goals, we developed a new method for automated high throughput ChIP coupled to sequencing (HT-ChIP-Seq). We used this method to measure binding of 40 TFs in 4 time points following stimulation of dendritic cells with pathogen components. We find that TFs vary substantially in their binding dynamics, genomic localization, number of binding events, and degree of interaction with other TFs. The analysis of this data suggests that the TF network is hierarchically organized, and composed of different types of TFs, cell differentiation factors, factors that prime for gene induction, and factors that bind more specifically and dynamically. This proposal revisits and challenges the current understanding of the mammalian regulatory code.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym ELIMINATESENESCENT
Project The Role of Elimination of Senescent Cells in Cancer Development
Researcher (PI) Valery Krizhanovsky
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Summary
Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym EVODEVOPATHS
Project Evolution of Developmental Gene Pathways
Researcher (PI) Itai Yanai
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary The staggering diversity of the living world is a testament to the amount of variation available to the agency of natural selection. While it has been assumed that variation is entirely uniform and unbiased, recent work has challenged this notion. Evolutionary developmental biology seeks to understand the biases on variation imposed by developmental processes and their distinction from selective constraints. Metazoan development is best described by developmental gene pathways which are composed of transcription factors, signaling molecules, and terminal differentiation genes. A systematic comparison of such pathways across species would reveal the patterns of conservation and divergence; however this has not yet been achieved. In the EvoDevoPaths project we will develop a new approach to unravel pathways using both single-cell and tissue-specific transcriptomics. Our aim is to elucidate the evolution of developmental gene pathways using intricate embryology in the nematode phylum, a single-cell transcriptomic method we have developed, and sophisticated computational approaches for pathway comparisons. We will ask how variation is distributed across the specification and differentiation modules of a pathway using the nematode endoderm pathway as a model system. We further propose that the evolutionary change in the tissue specification pathways of early cell lineages is constrained by the properties of cell specification pathways. To test this hypothesis we will, for the first time, determine early developmental cell lineages from single cell transcriptomic data. Finally, we will attempt to unify the molecular signatures of conserved stages in disparate phyla under a framework in which they can be systematically compared. This research collectively represents the first time that developmental gene pathways are examined in an unbiased manner contributing to a theory of molecular variation that explains the evolutionary processes that underlie phenotypic novelty.
Summary
The staggering diversity of the living world is a testament to the amount of variation available to the agency of natural selection. While it has been assumed that variation is entirely uniform and unbiased, recent work has challenged this notion. Evolutionary developmental biology seeks to understand the biases on variation imposed by developmental processes and their distinction from selective constraints. Metazoan development is best described by developmental gene pathways which are composed of transcription factors, signaling molecules, and terminal differentiation genes. A systematic comparison of such pathways across species would reveal the patterns of conservation and divergence; however this has not yet been achieved. In the EvoDevoPaths project we will develop a new approach to unravel pathways using both single-cell and tissue-specific transcriptomics. Our aim is to elucidate the evolution of developmental gene pathways using intricate embryology in the nematode phylum, a single-cell transcriptomic method we have developed, and sophisticated computational approaches for pathway comparisons. We will ask how variation is distributed across the specification and differentiation modules of a pathway using the nematode endoderm pathway as a model system. We further propose that the evolutionary change in the tissue specification pathways of early cell lineages is constrained by the properties of cell specification pathways. To test this hypothesis we will, for the first time, determine early developmental cell lineages from single cell transcriptomic data. Finally, we will attempt to unify the molecular signatures of conserved stages in disparate phyla under a framework in which they can be systematically compared. This research collectively represents the first time that developmental gene pathways are examined in an unbiased manner contributing to a theory of molecular variation that explains the evolutionary processes that underlie phenotypic novelty.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym EVOEPIC
Project Evolutionary mechanisms of epigenomic and chromosomal aberrations in cancer
Researcher (PI) Amos Tanay
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary Our working hypothesis is that tumorigenesis is an evolutionary process that fundamentally couples few major driving events (point mutations, rearrangements) with a complex flux of minor aberrations, many of which are epigenetic. We believe that these minor events are critical factors in the emergence of the cancer phenotype, and that understanding them is essential to the characterization of the disease. In particular, we hypothesize that a quantitative and principled evolutionary model for carcinogenesis is imperative for understanding the heterogeneity within tumor cell populations and predicting the effects of cancer therapies. We will therefore develop an interdisciplinary scheme that combines theoretical models of cancer evolution with in vitro evolutionary experiments and new methods for assaying the population heterogeneity of epigenomic organization. By developing techniques to interrogate DNA methylation and its interaction with other key epigenetic marks at the single-cell level, we will allow quantitative theoretical predictions to be scrutinized and refined. By combining models describing epigenetic aberrations with direct measurements of chromatin organization using Hi-C and 4C-seq, we shall revisit fundamental questions on the causative nature of epigenetic changes during carcinogenesis. Ultimately, we will apply both theoretical and experimental methodologies to assay and characterize the evolutionary histories of tumor cell populations from multiple mouse models and clinical patient samples.
Summary
Our working hypothesis is that tumorigenesis is an evolutionary process that fundamentally couples few major driving events (point mutations, rearrangements) with a complex flux of minor aberrations, many of which are epigenetic. We believe that these minor events are critical factors in the emergence of the cancer phenotype, and that understanding them is essential to the characterization of the disease. In particular, we hypothesize that a quantitative and principled evolutionary model for carcinogenesis is imperative for understanding the heterogeneity within tumor cell populations and predicting the effects of cancer therapies. We will therefore develop an interdisciplinary scheme that combines theoretical models of cancer evolution with in vitro evolutionary experiments and new methods for assaying the population heterogeneity of epigenomic organization. By developing techniques to interrogate DNA methylation and its interaction with other key epigenetic marks at the single-cell level, we will allow quantitative theoretical predictions to be scrutinized and refined. By combining models describing epigenetic aberrations with direct measurements of chromatin organization using Hi-C and 4C-seq, we shall revisit fundamental questions on the causative nature of epigenetic changes during carcinogenesis. Ultimately, we will apply both theoretical and experimental methodologies to assay and characterize the evolutionary histories of tumor cell populations from multiple mouse models and clinical patient samples.
Max ERC Funding
1 499 998 €
Duration
Start date: 2012-12-01, End date: 2017-11-30
Project acronym Gendever
Project Genome, the Edited Version: DNA and RNA Editing of Mammalian Retroelements
Researcher (PI) Erez Levanon
Host Institution (HI) BAR ILAN UNIVERSITY
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary It is generally thought that an organism contains the exactly same genomic information in all its cells and that a genome remains unaltered throughout the organism’s life, with the exception of rare and random somatic mutations that might occur. This genomic information will also serve as a template for exact RNA copies. However, endogenous and powerful means of creating inner genomic diversity are known to exist: (1) RNA editing that leads to alteration of one nucleotide into another, (mainly A-to-I); (2) DNA editing that changes the DNA’s content by shifting C-into-U; (3) active retroelements that can insert copies of their sequences into new locations in a genome.
Recently, we and others have found that although considered extremely rare, all three mechanisms are active somatically or at least leave traces of their occurrence in the genome, and are linked together, as most editing events occur in retroelements. However, the magnitude and scope of these mechanisms, which can lead to huge diversity and complexity within an organism and even within a cell, are still a mystery. This explosion of genomic variety can have dramatic effect on diverse biological processes, such as brain complexity, cancer and evolution acceleration.
In GENEDVER, we aim to perform the first genome-wide mapping of editing and active retroelements in various genomes using a combination of computational and genomic approaches. Specifically, we will develop a strategy to detect RNA and DNA editing in retroelements, scan for editing events in various genomes, and build the first global editing atlas. In addition, we will exploit the close association between editing and retroelements in to produce a genome-wide approach to detect active retroelements. Finally, we will screen for editing events and retrotranspositions in various biological conditions, in order to expose their involvement in many biological states and evolution.
Summary
It is generally thought that an organism contains the exactly same genomic information in all its cells and that a genome remains unaltered throughout the organism’s life, with the exception of rare and random somatic mutations that might occur. This genomic information will also serve as a template for exact RNA copies. However, endogenous and powerful means of creating inner genomic diversity are known to exist: (1) RNA editing that leads to alteration of one nucleotide into another, (mainly A-to-I); (2) DNA editing that changes the DNA’s content by shifting C-into-U; (3) active retroelements that can insert copies of their sequences into new locations in a genome.
Recently, we and others have found that although considered extremely rare, all three mechanisms are active somatically or at least leave traces of their occurrence in the genome, and are linked together, as most editing events occur in retroelements. However, the magnitude and scope of these mechanisms, which can lead to huge diversity and complexity within an organism and even within a cell, are still a mystery. This explosion of genomic variety can have dramatic effect on diverse biological processes, such as brain complexity, cancer and evolution acceleration.
In GENEDVER, we aim to perform the first genome-wide mapping of editing and active retroelements in various genomes using a combination of computational and genomic approaches. Specifically, we will develop a strategy to detect RNA and DNA editing in retroelements, scan for editing events in various genomes, and build the first global editing atlas. In addition, we will exploit the close association between editing and retroelements in to produce a genome-wide approach to detect active retroelements. Finally, we will screen for editing events and retrotranspositions in various biological conditions, in order to expose their involvement in many biological states and evolution.
Max ERC Funding
1 499 249 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
