Project acronym FastBio
Project A genomics and systems biology approach to explore the molecular signature and functional consequences of long-term, structured fasting in humans
Researcher (PI) Antigoni DIMA
Host Institution (HI) BIOMEDICAL SCIENCES RESEARCH CENTER ALEXANDER FLEMING
Call Details Starting Grant (StG), LS2, ERC-2016-STG
Summary Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.
Summary
Dietary intake has an enormous impact on aspects of human health, yet scientific consensus about how what we eat affects our biology remains elusive. To address the complex biological impact of diet, I propose to apply an unconventional, ‘humans-as-model-organisms’ approach to compare the molecular and functional effects of a highly structured dietary regime, specified by the Eastern Orthodox Christian Church (EOCC), to the unstructured diet followed by the general population. Individuals who follow the EOCC regime abstain from meat, dairy products and eggs for 180-200 days annually, in a temporally-structured manner initiated in childhood. I aim to explore the biological signatures of structured vs. unstructured diet by addressing three objectives. First I will investigate the effects of the two regimes, and of genetic variation, on higher-level phenotypes including anthropometric, physiological and biomarker traits. Second, I will carry out a comprehensive set of omics assays (metabolomics, transcriptomics, epigenomics and investigation of the gut microbiome), will associate omics phenotypes with genetic variation, and will integrate data across biological levels to uncover complex molecular signatures. Third, I will interrogate the functional consequences of dietary regimes at the cellular level through primary cell culture. Acute and long-term effects of dietary intake will be explored for all objectives through a two timepoint sampling strategy. This proposal therefore comprises a unique opportunity to study a specific perturbation (EOCC structured diet) introduced to a steady-state system (unstructured diet followed by the general population) in a ground-breaking human systems biology type of study. This approach brings together expertise from genomics, computational biology, statistics, medicine and epidemiology. It will lead to novel insights regarding the potent signalling nature of nutrients and is likely to yield results of high translational value.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym MaintainMeth
Project Quantitative analysis of DNA methylation maintenance within chromatin
Researcher (PI) Daniel ZILBERMAN
Host Institution (HI) JOHN INNES CENTRE
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary Cytosine methylation is a chemical modification that is precisely copied when DNA is replicated. Because methylation can regulate gene expression, accurate reproduction of DNA methylation patterns is essential for plant and animal development and for human health. The enzymes that maintain DNA methylation have to work within chromatin, and particularly to contend with nucleosomes – tight complexes of DNA and histone proteins. How methylation of nucleosomal DNA is maintained remains unknown, and even the simple matter of whether nucleosomes hinder or promote methylation is controversial.
My laboratory’s recent work with DDM1 – an ancient protein conserved between plants and animals that can move nucleosomes – and linker histone H1, which binds to nucleosomes and the intervening ‘linker’ DNA, has allowed us to formulate a model wherein movement of nucleosomes by DDM1 dislodges H1 and allows methyltransferases to access the DNA. Furthermore, this work revealed the existence of unknown factors required to maintain DNA methylation. My laboratory also discovered that DNA methylation influences nucleosome placement, thereby demonstrating that the interaction between DNA methylation and nucleosomes is bidirectional.
My goal is now to deeply understand the connected processes of maintenance methylation and nucleosome placement. This will be achieved through three interconnected research strands:
1) Elucidation of how DNA methylation is maintained within chromatin.
2) Identification of new DNA methylation maintenance factors.
3) Determination of how DNA methylation influences nucleosomes in vivo.
Our ultimate output will be the creation of a mathematical model of DNA methylation maintenance that will incorporate the bidirectional interactions between methylation and nucleosomes. This breakthrough will revolutionize research in the field by permitting the development of precise, quantitative hypotheses about the maintenance and function of DNA methylation within chromatin.
Summary
Cytosine methylation is a chemical modification that is precisely copied when DNA is replicated. Because methylation can regulate gene expression, accurate reproduction of DNA methylation patterns is essential for plant and animal development and for human health. The enzymes that maintain DNA methylation have to work within chromatin, and particularly to contend with nucleosomes – tight complexes of DNA and histone proteins. How methylation of nucleosomal DNA is maintained remains unknown, and even the simple matter of whether nucleosomes hinder or promote methylation is controversial.
My laboratory’s recent work with DDM1 – an ancient protein conserved between plants and animals that can move nucleosomes – and linker histone H1, which binds to nucleosomes and the intervening ‘linker’ DNA, has allowed us to formulate a model wherein movement of nucleosomes by DDM1 dislodges H1 and allows methyltransferases to access the DNA. Furthermore, this work revealed the existence of unknown factors required to maintain DNA methylation. My laboratory also discovered that DNA methylation influences nucleosome placement, thereby demonstrating that the interaction between DNA methylation and nucleosomes is bidirectional.
My goal is now to deeply understand the connected processes of maintenance methylation and nucleosome placement. This will be achieved through three interconnected research strands:
1) Elucidation of how DNA methylation is maintained within chromatin.
2) Identification of new DNA methylation maintenance factors.
3) Determination of how DNA methylation influences nucleosomes in vivo.
Our ultimate output will be the creation of a mathematical model of DNA methylation maintenance that will incorporate the bidirectional interactions between methylation and nucleosomes. This breakthrough will revolutionize research in the field by permitting the development of precise, quantitative hypotheses about the maintenance and function of DNA methylation within chromatin.
Max ERC Funding
2 749 962 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym PATHORISC
Project Reprogramming of small RNA function in plant-pathogen interactions
Researcher (PI) Anders Peter BRODERSEN
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary RNA silencing relies on small RNAs that act in RNA induced silencing complexes (RISCs). RISCs use base pairing to select mRNAs or invading nucleic acids such as viruses for repression. RNA silencing may facilitate gene expression changes, for example in host-pathogen interactions. Such changes require reprogramming of RISC, since a different set of RNAs must be rapidly repressed upon pathogen perception. RISC reprogramming is non-trivial: new small RNAs must be produced and be rapidly incorporated into RISC, while unwanted repression by pre-existing RISCs must be eliminated. This project focuses on understanding three central aspects of RISC reprogramming in plant-pathogen interactions. First, we will define mechanisms that allow invading RNA, but not self-RNA, to engage in positive feedback loops for small RNA synthesis, and we will investigate the specific importance of these positive feedback loops in antiviral defense. Second, we will explore how rapid proteolysis of the central RISC component ARGONAUTE1 (AGO1) governs rapid incorporation of newly synthesized small RNA. We will also explore the hypothesis that non-RNA bound AGO1 is degraded to minimize vulnerability to pathogens that use small RNAs as virulence factors to repress host immune signaling. The relevance of these mechanisms of AGO1 proteolysis in plant immunity will be investigated. These studies take advantage of our recent discovery of proteins required specifically for turnover of AGO1. Finally, we explore the hypothesis that rapid chemical modification of mRNA by N6-adenosine methylation (m6A) may bring mRNAs with poor small RNA binding sites under RISC repression. This scenario is supported by interactions between m6A reader proteins and AGO1 discovered in current work in the group. This mechanism may enable reprogramming of RISC specificity rather than composition upon pathogen perception. Our project will fill gaps in knowledge on RNA silencing and elucidate their importance in plant immunity.
Summary
RNA silencing relies on small RNAs that act in RNA induced silencing complexes (RISCs). RISCs use base pairing to select mRNAs or invading nucleic acids such as viruses for repression. RNA silencing may facilitate gene expression changes, for example in host-pathogen interactions. Such changes require reprogramming of RISC, since a different set of RNAs must be rapidly repressed upon pathogen perception. RISC reprogramming is non-trivial: new small RNAs must be produced and be rapidly incorporated into RISC, while unwanted repression by pre-existing RISCs must be eliminated. This project focuses on understanding three central aspects of RISC reprogramming in plant-pathogen interactions. First, we will define mechanisms that allow invading RNA, but not self-RNA, to engage in positive feedback loops for small RNA synthesis, and we will investigate the specific importance of these positive feedback loops in antiviral defense. Second, we will explore how rapid proteolysis of the central RISC component ARGONAUTE1 (AGO1) governs rapid incorporation of newly synthesized small RNA. We will also explore the hypothesis that non-RNA bound AGO1 is degraded to minimize vulnerability to pathogens that use small RNAs as virulence factors to repress host immune signaling. The relevance of these mechanisms of AGO1 proteolysis in plant immunity will be investigated. These studies take advantage of our recent discovery of proteins required specifically for turnover of AGO1. Finally, we explore the hypothesis that rapid chemical modification of mRNA by N6-adenosine methylation (m6A) may bring mRNAs with poor small RNA binding sites under RISC repression. This scenario is supported by interactions between m6A reader proteins and AGO1 discovered in current work in the group. This mechanism may enable reprogramming of RISC specificity rather than composition upon pathogen perception. Our project will fill gaps in knowledge on RNA silencing and elucidate their importance in plant immunity.
Max ERC Funding
1 987 811 €
Duration
Start date: 2017-05-01, End date: 2022-04-30
Project acronym ReCAP
Project Repair capacity and genome diversity in mammals
Researcher (PI) Eva Ran Hoffmann
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Consolidator Grant (CoG), LS2, ERC-2016-COG
Summary Genome evolution is driven by the generation of diversity. In mammals, genome diversification occurs in germline during the specialised division (meiosis) in gametes, when chromosomes recombine and assort into new haploid sets as they are passed from parent to offspring. Recently, the traditional view that genome diversification occurs exclusively in the germline has been challenged by findings that mutations in early embryos may cause predisposition to childhood cancers. We are uniquely placed to explore genome diversification in the germline and early embryos due to our breakthroughs in developing single-cell genomics and reproductive technologies.
Our strategic aim is to uncover the capacity for genetic diversity in the human genome and investigate how DNA repair capacity in adult oocytes and early embryos facilitates genome stability. This will allow us to identify the selective forces that shape the genomic landscape in humans. Based on preliminary data, we hypothesize that repair capacity determines reproductive fitness of mammalian females, and that impaired repair capacity may underlie infertility, miscarriage, and congenital disorders. In Objective 1 we focus on adult oocytes, their survival in the adult ovary and the maintenance of genetic quality as women age. Objective 2 investigates genome diversification and stability in early embryos and putative ‘self-corrective’ mechanisms that restore the genetic quality of embryos. This proposal will shed light on a poorly understood area of enormous socioeconomic and medical importance.
Summary
Genome evolution is driven by the generation of diversity. In mammals, genome diversification occurs in germline during the specialised division (meiosis) in gametes, when chromosomes recombine and assort into new haploid sets as they are passed from parent to offspring. Recently, the traditional view that genome diversification occurs exclusively in the germline has been challenged by findings that mutations in early embryos may cause predisposition to childhood cancers. We are uniquely placed to explore genome diversification in the germline and early embryos due to our breakthroughs in developing single-cell genomics and reproductive technologies.
Our strategic aim is to uncover the capacity for genetic diversity in the human genome and investigate how DNA repair capacity in adult oocytes and early embryos facilitates genome stability. This will allow us to identify the selective forces that shape the genomic landscape in humans. Based on preliminary data, we hypothesize that repair capacity determines reproductive fitness of mammalian females, and that impaired repair capacity may underlie infertility, miscarriage, and congenital disorders. In Objective 1 we focus on adult oocytes, their survival in the adult ovary and the maintenance of genetic quality as women age. Objective 2 investigates genome diversification and stability in early embryos and putative ‘self-corrective’ mechanisms that restore the genetic quality of embryos. This proposal will shed light on a poorly understood area of enormous socioeconomic and medical importance.
Max ERC Funding
1 997 593 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
